2-202556321-C-T

Position:

chr2-202556321-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.2656C>T variant is a missense variant predicted to cause an arginine to cysteine substitution at amino acid position 886. The highest population minor allele frequency in gnomAD v.2.1.1 controls is 0.1130% (11/9738 alleles) in the African/African American population. The population evidence available meets the threshold for BS1 (≥0.1%), but not for BA1 (>5%) or PM2 (<0.01%) as defined by the ClinGen Pulmonary Hypertension VCEP (PH-VCEP). Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.485 indicating that neither BP4 or PP3 were met since the threshold specified by the PH-VCEP is <0.25 and >0.75, respectively. The amino acid substitution occurs in the c-terminal domain, which is not a well-established functional domain, so PM1 was not met. Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation data. BS3 and PS3 were not evaluated due to the lack of functional data for this variant. In summary, the variant meets the criteria to be classified as likely benign (LB) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061559/MONDO:0015924/125

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

BMPR2
NM_001204.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.90

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.

BS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7 linkuse as main transcript	c.2656C>T	p.Arg886Cys	missense_variant	12/13	ENST00000374580.10
BMPR2	XM_011511687.2 linkuse as main transcript	c.2656C>T	p.Arg886Cys	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10 linkuse as main transcript	c.2656C>T	p.Arg886Cys	missense_variant	12/13	1	NM_001204.7	P1	Q13873-1
BMPR2	ENST00000374574.2 linkuse as main transcript	c.1587-3375C>T		intron_variant		2			Q13873-2

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000103

AC:

AN:

251458

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000374

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000743

Hom.:

Bravo

AF:

0.000397

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2021

The p.R886C variant (also known as c.2656C>T), located in coding exon 12 of the BMPR2 gene, results from a C to T substitution at nucleotide position 2656. The arginine at codon 886 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Pulmonary arterial hypertension

Benign:1

Likely benign, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Sep 10, 2024

The BMPR2 c.2656C>T variant is a missense variant predicted to cause an arginine to cysteine substitution at amino acid position 886. The highest population minor allele frequency in gnomAD v.2.1.1 controls is 0.1130% (11/9738 alleles) in the African/African American population. The population evidence available meets the threshold for BS1 (≥0.1%), but not for BA1 (>5%) or PM2 (<0.01%) as defined by the ClinGen Pulmonary Hypertension VCEP (PH-VCEP). Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.485 indicating that neither BP4 or PP3 were met since the threshold specified by the PH-VCEP is <0.25 and >0.75, respectively. The amino acid substitution occurs in the c-terminal domain, which is not a well-established functional domain, so PM1 was not met. Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation data. BS3 and PS3 were not evaluated due to the lack of functional data for this variant. In summary, the variant meets the criteria to be classified as likely benign (LB) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024). -

Primary pulmonary hypertension

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.23

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.64

MVP

0.93

MPC

1.2

ClinPred

0.095

GERP RS

6.2

Varity_R

0.31

gMVP

0.25

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