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_000022.4(ADA):c.1078+2T>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA409118267

2088001 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c725d9fb-072d-4ecf-af7f-5c7c18f04344

Approved on: 2024-01-23

Published on: 2024-01-23

HGVS expressions

NM_000022.4:c.1078+2T>C

NM_000022.4(ADA):c.1078+2T>C

NC_000020.11:g.44620297A>G

CM000682.2:g.44620297A>G

NC_000020.10:g.43248938A>G

CM000682.1:g.43248938A>G

NC_000020.9:g.42682352A>G

NG_007385.1:g.36439T>C

ENST00000372874.9:c.1078+2T>C

ENST00000372874.8:c.1078+2T>C

ENST00000372887.5:c.152-3636A>G

ENST00000464097.5:n.1444+2T>C

ENST00000492931.5:n.1238+2T>C

ENST00000536532.5:c.*221+2T>C

ENST00000537820.1:c.1006+2T>C

ENST00000539235.5:c.*462+2T>C

NM_000022.2:c.1078+2T>C

NM_000022.3:c.1078+2T>C

NM_001322050.1:c.673+2T>C

NM_001322051.1:c.1006+2T>C

NR_136160.1:n.1164+2T>C

NM_001322050.2:c.673+2T>C

NM_001322051.2:c.1006+2T>C

NR_136160.2:n.1105+2T>C

Uncertain Significance

PM2_Supporting PS1_Moderate PVS1_Moderate

BS2

Evidence Links 0

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ADA Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The c.1078+2T>C (NM_000022.4) variant in ADA occurs within the canonical splice donor site (+2) of intron 11. It is predicted to cause skipping of biologically relevant exon by SpliceAI (Δ score = Donor Loss = 0.96); however, due to the location, it is NOT predicted to undergo NMD. There aren't known downstream pathogenic variants; Variant removes <10% of protein. PVS1_Moderate. This variant is absent from gnomAD v.4 (PM2_Supporting). The intronic change (c.1078+2T>A) is classified as Likely Pathogenic for ADA-SCID by the ClinGen SCID VCEP (PS1_Moderate). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies. In summary, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Moderate, PM2_Supporting, and PS1_Modetate (VCEP specifications version 1).

PM2_Supporting

This variant is absent from gnomAD v.4 (PM2_Supporting).

PS1_Moderate

The intronic change (c.1078+2T>A) is classified as Likely Pathogenic for ADA-SCID by the ClinGen SCID VCEP (PS1_Moderate).

PVS1_Moderate

BS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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