2-202556360-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001204.7(BMPR2):c.2695C>T(p.Arg899*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BMPR2
NM_001204.7 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 5.85

Publications

92 publications found

Variant links:

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

BMPR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-202556360-C-T is Pathogenic according to our data. Variant chr2-202556360-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7 link	c.2695C>T	p.Arg899*	stop_gained	Exon 12 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2 link	c.2695C>T	p.Arg899*	stop_gained	Exon 12 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10 link	c.2695C>T	p.Arg899*	stop_gained	Exon 12 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2 link	c.1587-3336C>T		intron_variant	Intron 11 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pulmonary hypertension, primary, 1

Pathogenic:3

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Feb 07, 2025

Pharmacogenomics Laboratory, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The nonsense variant c.2695C>T (p.Arg899X) was detected in heterozygosis in the patient, who was diagnosed with hereditary PAH due to having an affected relative (nephew). The variant is not reported in the gnomAD population database. Arg899X has been demonstrated non-critical/not necessary for kinase activity based on the criteria of the ClinGen Pulmonary Hypertension Expert Panel (https://cspec.genome.network/cspec/ui/svi/doc/GN125). ClinVar classifies this variant as Pathogenic, 2 stars (reviewed Nov '24, 7 submissions). Based on available information, this variant is considered to be pathogenic.

Sep 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Pulmonary arterial hypertension

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

Dec 16, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BMPR2 c.2695C>T; p.Arg899Ter variant (rs137852741) is reported in the literature in multiple individuals affected with PAH (International PPH Consortium 2000, Machado 2009). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: International PPH Consortium. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000 Sep;26(1):81-4. Machado RD et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S32-42.

Primary pulmonary hypertension

Pathogenic:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg899*) in the BMPR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BMPR2 are known to be pathogenic (PMID: 16429395). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pulmonary hypertension (PMID: 10973254, 11115378, 15146475, 19555857, 21737554, 21801371, 23592887). In at least one individual the variant was observed to be de novo. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this BMPR2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 19,619 individuals referred to our laboratory for BMPR2 testing. ClinVar contains an entry for this variant (Variation ID: 8796). For these reasons, this variant has been classified as Pathogenic.

Pulmonary arterial hypertension;C5679820:Idiopathic and/or familial pulmonary arterial hypertension

Other:1

Wendy Chung Laboratory, Boston Children's Hospital

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.56

PhyloP100

5.9

Vest4

0.96

GERP RS

5.3

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over