Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_001204.7(BMPR2):c.2887G>T (p.Gly963Cys)

CA2061614

333651 (ClinVar)

Gene: BMPR2
Condition: pulmonary arterial hypertension
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9b757254-9aea-4dfa-8304-74a9c6d0491a
Approved on: 2024-05-02
Published on: 2024-05-02

HGVS expressions

NM_001204.7:c.2887G>T
NM_001204.7(BMPR2):c.2887G>T (p.Gly963Cys)
NC_000002.12:g.202559716G>T
CM000664.2:g.202559716G>T
NC_000002.11:g.203424439G>T
CM000664.1:g.203424439G>T
NC_000002.10:g.203132684G>T
NG_009363.1:g.188390G>T
ENST00000374580.10:c.2887G>T
ENST00000638587.1:c.2818G>T
ENST00000374574.2:c.*14G>T
ENST00000374580.8:c.2887G>T
NM_001204.6:c.2887G>T

Likely Benign

Met criteria codes 1
BS1
Not Met criteria codes 6
BP4 PS4 PP3 BA1 PM2 PM1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Pulmonary Hypertension Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Pulmonary Hypertension VCEP
The BMPR2 c.2887G>T variant is a missense variant predicted to cause a glycine to cysteine substitution at amino acid 963 (p.Gly963Cys). The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.001015 (13/12804 alleles) in the Swedish population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold of >0.1% for BS1, and therefore meets this criterion (BS1). PP3 was not met as the computational predictor, REVEL, gives a score of 0.418, which is below the threshold of 0.75 (and above the threshold of >=0.25 for PP3). No functional data was available for review and SpliceAI did not predict an effect on splicing. In summary, the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024).
Met criteria codes
BS1
The variant is found in the Swedish population on gnomAD v2.1.1 (controls) with a frequency of 0.0010 (13/12804).
Not Met criteria codes
BP4
The REVEL score for this variant is 0.418, which is above the threshold of 0.25 defined by the PH VCEP. SpliceAI did not indicate a predicted effect on splicing
PS4
Based on the PH VCEP, PM2_Supporting must be met prior to applying PS4. Since this variant is present in the control population of gnomAD v2.1.1 at a frequency higher than the cut-off of 0.01% for PAH, PM2_supporting is not met. Therefore, we cannot apply PS4.
PP3
The REVEL score for this variant is 0.418, which is below the threshold of 0.75 defined by the PH VCEP. SpliceAI did not indicate a predicted effect on splicing
BA1
BS1 is met
PM2
The variant is found in the Swedish population on gnomAD v2.1.1 (controls) with a frequency above the cut-off of 0.01% for PAH.
PM1
The amino acid change that results from this variant is outside of the critical extracellular and kinase domains.
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