Variant chr2-202513739-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001204.7(BMPR2):c.439C>T(p.Arg147*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,574 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:6O:1

Conservation

PhyloP100: 1.60

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 2-202513739-C-T is Pathogenic according to our data. Variant chr2-202513739-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 222513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7 linkuse as main transcript	c.439C>T	p.Arg147*	stop_gained	4/13	ENST00000374580.10	NP_001195.2	Q13873-1
BMPR2	XM_011511687.2 linkuse as main transcript	c.439C>T	p.Arg147*	stop_gained	4/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10 linkuse as main transcript	c.439C>T	p.Arg147*	stop_gained	4/13	1	NM_001204.7	ENSP00000363708.4		Q13873-1
BMPR2	ENST00000374574.2 linkuse as main transcript	c.439C>T	p.Arg147*	stop_gained	4/12	2		ENSP00000363702.2		Q13873-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251204

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460574

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726656

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pulmonary hypertension, primary, 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 07, 2015	- -
Pathogenic, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	-	- -

Pulmonary arterial hypertension

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 01, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2024

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26387786, 32634488, 35346192, 32581362, 20534176, 14526373, 16717148, 20002458, 16429395, 15146475, 25612240, 25525159, 21801371, 11115378, 29743074, 29023671, 30578397, 18356561, 31727138, 18503968, 21737554) -

Primary pulmonary hypertension

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change creates a premature translational stop signal (p.Arg147*) 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 present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with pulmonary hypertension (PMID: 11115378, 15146475, 16717148, 18503968, 30578397). ClinVar contains an entry for this variant (Variation ID: 222513). For these reasons, this variant has been classified as Pathogenic. -

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

Other:1

not provided, no classification provided

literature only

Wendy Chung Laboratory, Columbia University Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.92

Vest4

0.97

GERP RS

4.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over