chr2-202530791-C-G

Variant names:

• chr2-202530791-C-G
• rs1085307280
• NM_001204.7:c.968-3C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.968-3C>G is an intronic variant in intron 7. This variant is absent from both gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The variant has been reported in 2 unrelated PAH patients (PMID:26387786 and GeneDx submission to ClinVar) (PS4_Supporting). PVS1 is not applied because it is a non-canonical splice site variant without mRNA processing data. The computational splicing predictor SpliceAI gives a score of 0.98 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 7 (PP3). In summary, the variant is classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PS4_supporting, PP3 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA645293968/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 1.15
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.968-3C>G		splice_region_variant, intron_variant	Intron 7 of 12	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.968-3C>G		splice_region_variant, intron_variant	Intron 7 of 12		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.968-3C>G		splice_region_variant, intron_variant	Intron 7 of 12	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.968-3C>G		splice_region_variant, intron_variant	Intron 7 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

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

- -

Pulmonary arterial hypertension Uncertain:1

May 03, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The BMPR2 c.968-3C>G is an intronic variant in intron 7. This variant is absent from both gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The variant has been reported in 2 unrelated PAH patients (PMID: 26387786 and GeneDx submission to ClinVar) (PS4_Supporting). PVS1 is not applied because it is a non-canonical splice site variant without mRNA processing data. The computational splicing predictor SpliceAI gives a score of 0.98 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 7 (PP3). In summary, the variant is classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PS4_supporting, PP3 (VCEP specification version 1.1, 1/18/2024). -

not provided Uncertain:1

Dec 12, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 26387786) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Benign	0.90
PhyloP100		1.1
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: 1
DS_AL_spliceai		0.98		Position offset: 3

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

Other links and lift over

dbSNP: rs1085307280; hg19: chr2-203395514;