2-202464950-C-G

Variant names:

• chr2-202464950-C-G
• rs137852742
• NM_001204.7:c.218C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.218C>G, (p.Ser73Ter) (NM_001204.7) variant in BMPR2 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:16429395). This variant has been reported in 2 pulmonary arterial hypertension probands (PS4_Supporting) (PMID:26387786 ; PMID:32581362). This variant is absent from gnomAD v2.1.1 controls (PM2_Supporting). In summary, this 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 (specification version 11, 1/18/2024): PVS1, PS4_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA278072/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 3.01
• Publications: 2 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 10 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.218C>G	p.Ser73*	stop_gained	Exon 2 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.218C>G	p.Ser73*	stop_gained	Exon 2 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.218C>G	p.Ser73*	stop_gained	Exon 2 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.218C>G	p.Ser73*	stop_gained	Exon 2 of 12	2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.125C>G		non_coding_transcript_exon_variant	Exon 1 of 3	3

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:2

May 03, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.218C>G, (p.Ser73Ter) (NM_001204.7) variant in BMPR2 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 16429395). This variant has been reported in 2 pulmonary arterial hypertension probands (PS4_Supporting) (PMID: 26387786 ; PMID: 32581362). This variant is absent from gnomAD v2.1.1 controls (PM2_Supporting). In summary, this 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 (specification version 11, 1/18/2024): PVS1, PS4_Supporting, PM2_Supporting. -

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NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Pulmonary hypertension, primary, 1 Pathogenic:1

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		3.0
Vest4		0.94
GERP RS		5.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137852742; hg19: chr2-203329673;