2-202552811-A-C

Position:

chr2-202552811-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS3

This summary comes from the ClinGen Evidence Repository: The NM_001204.7(BMPR2) c.1509A>C variant is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 503 (p.Glu503Asp). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.0001105 (1/9046 alleles) in East Asian population, which is higher than the ClinGen PH VCEP threshold (<0.01%) for PM2 but lower than the threshold (>0.1%) for BS1. Therefore, this variant does not meet either of these population criteria. The computational predictor REVEL gives a score of 0.662, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function. Luciferase assay data indicated that variant transcriptional activity was comparable to wild-type, indicating no deleterious effect (BS3; PMID:18321866). The p.Glu503Asp (p.E503D) mutant also shows normal localization to the plasma membrane (PMID:25688877) and no effect on cell viability (PMID:30809644). In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS3. (VCEP specifications version 1.1, 1/18/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16610570/MONDO:0015924/125

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BMPR2
NM_001204.7 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel P:1U:2B:2

Conservation

PhyloP100: 1.92

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 Likely_benign. Variant got -4 ACMG points.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7 link	c.1509A>C	p.Glu503Asp	missense_variant	11/13	ENST00000374580.10	NP_001195.2	Q13873-1
BMPR2	XM_011511687.2 link	c.1509A>C	p.Glu503Asp	missense_variant	11/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10 link	c.1509A>C	p.Glu503Asp	missense_variant	11/13	1	NM_001204.7	ENSP00000363708.4		Q13873-1
BMPR2	ENST00000374574.2 link	c.1509A>C	p.Glu503Asp	missense_variant	11/12	2		ENSP00000363702.2		Q13873-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251488

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pulmonary arterial hypertension associated with congenital heart disease

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	-	- -
Uncertain significance, criteria provided, single submitter	case-control	Wendy Chung Laboratory, Columbia University Medical Center	Jun 27, 2018	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 09, 2022

- -

Pulmonary arterial hypertension

Benign:1

Likely benign, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Sep 20, 2024

The NM_001204.7(BMPR2) c.1509A>C variant is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 503 (p.Glu503Asp). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.0001105 (1/9046 alleles) in East Asian population, which is higher than the ClinGen PH VCEP threshold (<0.01%) for PM2 but lower than the threshold (>0.1%) for BS1. Therefore, this variant does not meet either of these population criteria. The computational predictor REVEL gives a score of 0.662, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function. Luciferase assay data indicated that variant transcriptional activity was comparable to wild-type, indicating no deleterious effect (BS3; PMID: 18321866). The p.Glu503Asp (p.E503D) mutant also shows normal localization to the plasma membrane (PMID: 25688877) and no effect on cell viability (PMID: 30809644). In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS3. (VCEP specifications version 1.1, 1/18/2024) -

Primary pulmonary hypertension

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

D;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.010

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.092

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.77

N;N;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

N;N;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.026

D;T;.

Sift4G

Uncertain

0.037

D;T;.

Polyphen

0.53

P;.;.

Vest4

0.79

MutPred

0.84

Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);.;

MVP

0.99

MPC

0.34

ClinPred

0.36

GERP RS

3.2

Varity_R

0.67

gMVP

0.65

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

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