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_001204.7(BMPR2):c.529+2T>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA350338507

425800 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 26778d12-b52a-42a4-9b61-c6e1048a2505

Approved on: 2024-05-03

Published on: 2024-05-03

HGVS expressions

NM_001204.7:c.529+2T>C

NM_001204.7(BMPR2):c.529+2T>C

NC_000002.12:g.202513831T>C

CM000664.2:g.202513831T>C

NC_000002.11:g.203378554T>C

CM000664.1:g.203378554T>C

NC_000002.10:g.203086799T>C

NG_009363.1:g.142505T>C

ENST00000374580.10:c.529+2T>C

ENST00000638587.1:c.460+2T>C

ENST00000374574.2:c.529+2T>C

ENST00000374580.8:c.529+2T>C

NM_001204.6:c.529+2T>C

Uncertain Significance

PM2_Supporting PVS1_Strong

PP3 PM4

Evidence Links 0

Expert Panel

Pulmonary Hypertension VCEP

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 NM_001204.7(BMPR2) c.529+2T>C variant is located in the canonical donor splice site of intron 4. It is predicted to cause skipping of biologically relevant exon 4 (111 bp), resulting in an in-frame deletion of amino acids Ser140-Thr176 within the transmembrane domain, that is predicted to escape nonsense-mediated decay (PVS1_strong). The predictions were recorded under PVS1, so PP3 was not applied to avoid double counting. Although the variant is predicted to cause a change in the length of the protein due to in-frame deletion, no functional data are available and thus PM4 was not applied. This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PM2_supporting. (VCEP specifications version 1.1, 1/18/2024)

PM2_Supporting

This variant is absent from gnomAD controls (v2.1.1 and v3.1.2)

PVS1_Strong

The variant (NM_001204.7 (BMPR2): c.529+2T>C) occurs within the canonical splice donor site (+2) of intron 4. Splice AI predicts loss of donor splice site (score 0.97) that may lead to skipping of biologically relevant exon 4 (111bp), resulting in an in-frame deletion of 37 amino acids (140-176) present in the transmembrane domain. No experimental data are available for this variant.

PP3

The computational splicing predictor Splice AI gives a score of (0.97) for donor splice site loss, predicting that the variant disrupts the donor splice site of intron 4 of BMPR2. However, the predictions were recorded under PVS1 so PP3 was not applied to avoid double counting.

PM4

The variant (NM_001204.7: c.529+2T>C) is predicted to cause a change in the length of the protein due to in-frame deletion of 37 amino acids (140-176). However, no functional data are available to support this prediction, which has been scored under PVS1.

Curation History

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