Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000517.6(HBA2):c.2del (p.Met1fs)

CA125662

15692 (ClinVar)

Gene: HBA2 (HGNC:3040)

Condition: HBA2-related alpha thalassemia spectrum (MONDO:0100562)

Inheritance Mode: Autosomal recessive inheritance

UUID: 2b0b3327-e61d-4879-b167-b7e7398f3b0c

Approved on: 2026-04-08

Published on: 2026-04-08

HGVS expressions

NM_000517.6(HBA2):c.2del (p.Met1fs)

NM_000517.6:c.2del

NC_000016.10:g.172914del

CM000678.2:g.172914del

NC_000016.9:g.222913del

CM000678.1:g.222913del

NC_000016.8:g.162913del

NG_000006.1:g.33777del

NG_059186.1:g.1264del

NG_059271.1:g.5068del

ENST00000251595.11:c.2del

ENST00000251595.10:c.2del

ENST00000397806.1:c.-46del

ENST00000482565.1:n.21del

NM_000517.4:c.2del

Pathogenic

PM2_Supporting PVS1 PP1 PM3_Strong PS4_Supporting

PS3 PM5

Evidence Links 0

Expert Panel

Hemoglobinopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBA2 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hemoglobinopathy VCEP

The NM_000517.6(HBA2):c.2del, p.(Met1fs), variant is an initiation codon loss predicted to cause loss of function of the protein [PVS1]. It has been reported in 3 individuals displaying a hematological phenotype consistent with α-thalassemia trait (reduced MCV and MCH with normal/increased RBC count), giving a total score of 0.55 [PS4_P; PMID 16116675; 9322079; 28620953]. This variant has been detected in two individuals with HbH disease. Both were compound heterozygous for the variant and a pathogenic variant (α0 --SEA) and were confirmed in trans by family testing; total PM3 points are 2 [PM3_S; PMID: 16116675; 9322079]. It has been reported to segregate with HbH disease phenotype in 2 affected family members from 2 families. The total number of unaffected segregations is 1, giving a LOD score of 1.33 [PP1; PMID: 16116675; 9322079]. The minor allele frequency in gnomAD v4.1 is 0.000007432 (2/269118 alleles), which is lower than the ClinGen Hemoglobinopathy VCEP threshold <0.0001 for PM2_Supporting, and therefore meets this criterion [PM2_P]. In summary, this variant meets the criteria to be classified as pathogenic for HBA2-related alpha thalassemia spectrum (MONDO:0100562) in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen Hemoglobinopathy VCEP (specification version 1.0.0): PVS1, PM3_S, PP1, PS4_P, PM2_P.

PM2_Supporting

The minor allele frequency in gnomAD v4.1 is 0.000007432 (2/269118) alleles, which is lower than the ClinGen Hemoglobinopathy VCEP threshold <0.0001 for PM2_Supporting, and therefore meets this criterion [PM2_P]

PVS1

The c.2delT, p.(Met1fs) variant in HBA2 is an initiation codon loss predicted to cause loss of function of the protein

PP1

The variant has been reported to segregate with Hb H disease phenotype in 2 affected family members from 2 families. The total number of unaffected segregations is 1. The LOD score is 1.33 [PMID: 16116675, 9322079].

PM3_Strong

This variant has been detected in two individuals with HbH disease. Both were compound heterozygous for the variant and a pathogenic variant (α0 --SEA) and were confirmed in trans by family testing. Total PM3 points are 2. [PMID: 16116675, PMID: 9322079].

PS4_Supporting

This variant has been reported in 1 proband meeting low MCV (77.5), low MCH (25.0), with normal red blood cell counts (5.03x10^12) and normal HbA2 (2.4), in one proband reported to meet α-thalassemia trait phenotype (low MCV: 74.7 and normal HbA2: 2.3), and in one other proband meeting low MCV (75.4) and low MCH (26.2). Total score is 0.55 (PMID 16116675; PMID 9322079, PMID: 28620953) PMID 16116675: Mum (αα/αc.2delTα): Low MCV (77.5), MCH (25.0), normal RBC (5.03x10^12), normal HbA2 (2.4) => 0.2 PMID 9322079: Mum (αα/αc.2delTα): Alpha-thal trait phenotype (stated in paper) Low MCV (74.7), normal Hb (12.2), normal HbA2 (2.3) => 0.2 PMID: 28620953: Two (2) mutation carriers: mean Hb: 12.7 ± 0.1; mean MCH: 26.2 ± 0.4; mean MCV: 91.2 ± 15.8 At least one of two will have low MCV (MCV: 91.2 ± 15.8 => 91.2-15.8=75.4) Hence low MCH (MCH 26.2 ± 0.4), low MCV (75.4) => 0.15x1=0.15

PS3

Hemoglobin electrophoresis showed a change in electrophoretic mobilities (13.6% Hb H=>β4 and 5% Hb Bart’s => γ4), indicating that this variant impacts protein function (PMID 16116675)

PM5

Three (3) different initiation codon loss variants (c.2T>C, p.Met1Thr; c.1delA, p.Met1fs; c.1A>G, p.Met1Val) in the same codon have been reported in patients with alpha thalassemia/HbH disease (ClinVar ID: 15643; 15694; 15645). However, these variants have not yet met the criteria to be classified as pathogenic with a 2-star review status by ClinVar

Curation History

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