2-202542302-A-G

Variant names:

• chr2-202542302-A-G
• rs1085307331
• NM_001204.7:c.1277-9A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS4_Moderate PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.1277-9A>G variant is a non-canonical splice site (-9) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in four cases (PMID:18356561, 20534176, 27613157) (PS4_moderate). In silico prediction (SpliceAI) indicates likely loss of the acceptor splice site (score = 0.97). cDNA analysis demonstrates an aberrant splice product leading to premature truncation (p.Gly426Aspfs*47) and, thus, likely nonsense mediated decay (PMID:18356561 and private communication: Soubrier) (PVS1 (RNA)). No familial segregation data were available. In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1 (RNA), PM2_supporting, PS4_moderate (VCEP specification version v1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA645293838/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 intron
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 2.31
• Publications: 1 publications found

Genes affected

BMPR2 (HGNC:1078): (bone morphogenetic protein receptor type 2) This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are members of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of two different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Mutations in this gene have been associated with primary pulmonary hypertension, both familial and fenfluramine-associated, and with pulmonary venoocclusive disease. [provided by RefSeq, May 2020]

BMPR2 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary hypertension, primary, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.1277-9A>G		intron_variant	Intron 9 of 12	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1277-9A>G		intron_variant	Intron 9 of 12		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1277-9A>G		intron_variant	Intron 9 of 12	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1277-9A>G		intron_variant	Intron 9 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

May 05, 2025

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The BMPR2 c.1277-9A>G variant is a non-canonical splice site (-9) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in four cases (PMID: 18356561, 20534176, 27613157) (PS4_moderate). In silico prediction (SpliceAI) indicates likely loss of the acceptor splice site (score = 0.97). cDNA analysis demonstrates an aberrant splice product leading to premature truncation (p.Gly426Aspfs*47) and, thus, likely nonsense mediated decay (PMID: 18356561 and private communication: Soubrier) (PVS1 (RNA)). No familial segregation data were available. In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1 (RNA), PM2_supporting, PS4_moderate (VCEP specification version v1.1, 1/18/2024). -

Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PS4 -

Pulmonary hypertension, primary, 1 Pathogenic:1

-

Rare Disease Genomics Group, St George's University of London

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.93
PhyloP100		2.3
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1
DS_AL_spliceai		0.97		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1085307331; hg19: chr2-203407025;