rs140683387

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BS1

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.276A>C variant is a missense variant predicted to cause substitution of glutamine to histidine at amino acid position 92 (p.(Gln92His)). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.001589 in the East Asian population (Korean) (BS1 met but not PM2 or BA1). Computational predictor REVEL score is 0.57, which is in between the PH-VCEP specified threshold of ≤0.25 and ≥0.75, so neither PP3 nor BP4 are met. This variant is located in the extracellular domain, critical for ligand binding (PM1 met), but does not affect a known critical or non-critical amino acid (no up- or downward adjustment for PM1). BS2 was not met due to absence of homozygous individuals (gnomAD v.2.1.1 controls). PS4 was not applied as PM2 was not met. PP1, PS2, PM6 were not met due to the absence of co-segregation data. PS3 and BS3 were not met due to the lack of experimental evidence. Although other variants in the same amino acid been reported, for pulmonary arterial hypertension, the variants were not deemed pathogenic or likely pathogenic by the PH-VCEP (PS1, PM5 not met). 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: BS1, PM1 (VCEP specification version 1.1.0, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061080/MONDO:0015924/125

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

BMPR2
NM_001204.7 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:5B:2

Conservation

PhyloP100: 0.115

Publications

9 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: Likely_benign. The variant received -2 ACMG points.

PM1

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

BS1

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 link	c.276A>C	p.Gln92His	missense_variant	Exon 3 of 13	ENST00000374580.10	NP_001195.2	Q13873-1
BMPR2	XM_011511687.2 link	c.276A>C	p.Gln92His	missense_variant	Exon 3 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BMPR2	ENST00000374580.10 link	c.276A>C	p.Gln92His	missense_variant	Exon 3 of 13	1	NM_001204.7	ENSP00000363708.4	Q13873-1
BMPR2	ENST00000374574.2 link	c.276A>C	p.Gln92His	missense_variant	Exon 3 of 12	2		ENSP00000363702.2	Q13873-2
BMPR2	ENST00000479069.1 link	n.183A>C		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000557

AC:

AN:

251434

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000828

AC:

117

AN:

1413464

Hom.:

Cov.:

AF XY:

0.0000822

AC XY:

AN XY:

705688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32328

American (AMR)

AF:

0.0000224

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25856

East Asian (EAS)

AF:

0.00294

AC:

116

AN:

39454

South Asian (SAS)

AF:

0.00

AC:

AN:

85256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1068002

Other (OTH)

AF:

0.00

AC:

AN:

58852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jun 19, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Present in two Japanese patients reported to have pulmonary arterial hypertension and in a patient with anomalous unilateral single pulmonary vein (Kabata et al., 2013; Koyama et al., 2014; Kobayashi et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29718794, 24583436, 23675998, 27002414) -

Mar 11, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP5 -

Pulmonary hypertension, primary, 1

Uncertain:2

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Uncertain:1

Nov 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pulmonary arterial hypertension

Benign:1

Nov 01, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The BMPR2 c.276A>C variant is a missense variant predicted to cause substitution of glutamine to histidine at amino acid position 92 (p.(Gln92His)). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.001589 in the East Asian population (Korean) (BS1 met but not PM2 or BA1). Computational predictor REVEL score is 0.57, which is in between the PH-VCEP specified threshold of ≤0.25 and ≥0.75, so neither PP3 nor BP4 are met. This variant is located in the extracellular domain, critical for ligand binding (PM1 met), but does not affect a known critical or non-critical amino acid (no up- or downward adjustment for PM1). BS2 was not met due to absence of homozygous individuals (gnomAD v.2.1.1 controls). PS4 was not applied as PM2 was not met. PP1, PS2, PM6 were not met due to the absence of co-segregation data. PS3 and BS3 were not met due to the lack of experimental evidence. Although other variants in the same amino acid been reported, for pulmonary arterial hypertension, the variants were not deemed pathogenic or likely pathogenic by the PH-VCEP (PS1, PM5 not met). 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: BS1, PM1 (VCEP specification version 1.1.0, 1/18/2024). -

Primary pulmonary hypertension

Benign:1

Jan 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.75

D;.;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.78

T;T;T

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.052

T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

0.0

N;N;.

PhyloP100

0.12

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.4

N;N;.

REVEL

Uncertain

0.57

Sift

Benign

0.31

T;T;.

Sift4G

Benign

0.26

T;T;.

Polyphen

0.0010

B;.;.

Vest4

0.38

MutPred

0.62

Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;

MVP

1.0

MPC

0.32

ClinPred

0.33

GERP RS

-0.45

Varity_R

0.22

gMVP

0.61

Mutation Taster

=5/95

disease causing

(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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rs140683387

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