rs1085307316

Variant names:

• chr2-202532684-G-A
• rs1085307316
• NM_001204.7:c.1228G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-202532684-G-A
• chr2-202532684-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1_Strong PS1_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.1228G>A variant is a missense variant predicted to cause a glycine to arginine substitution at amino acid position 410. The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). Gly410Arg is located in the catalytic kinase domain and Gly410 is a known critical residue (PM1_strong). The variant was reported in two manuscripts (PMID:26387786 and PMID:21737554) describing the same individual; no other probands with the variant were identified (PS4 not met). A different variant affecting the same amino acid, c.1228 G>C (p.Gly410Arg), has been reported and was classified by our expert panel as likely pathogenic (PS1_moderate). Other pathogenic missense variants causing a different amino acid change at the same residue have not been reported (PM5 is not met). The REVEL score is 0.984, which meets the ClinGen Pulmonary Hypertension VCEP pathogenicity threshold of >=0.75 (PP3 met, BP4 not met). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation data. Functional data was not available (BS3 and PS3 not evaluated). In summary, this variant meets the criteria to be classified as likely pathogenic (LP) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS1_moderate, PM1_strong, PM2_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350341903/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.64

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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	c.1228G>A	p.Gly410Arg	missense_variant	Exon 9 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1228G>A	p.Gly410Arg	missense_variant	Exon 9 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1228G>A	p.Gly410Arg	missense_variant	Exon 9 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1228G>A	p.Gly410Arg	missense_variant	Exon 9 of 12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

Jan 03, 2025

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The BMPR2 c.1228G>A variant is a missense variant predicted to cause a glycine to arginine substitution at amino acid position 410. The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). Gly410Arg is located in the catalytic kinase domain and Gly410 is a known critical residue (PM1_strong). The variant was reported in two manuscripts (PMID: 26387786 and PMID: 21737554) describing the same individual; no other probands with the variant were identified (PS4 not met). A different variant affecting the same amino acid, c.1228 G>C (p.Gly410Arg), has been reported and was classified by our expert panel as likely pathogenic (PS1_moderate). Other pathogenic missense variants causing a different amino acid change at the same residue have not been reported (PM5 is not met). The REVEL score is 0.984, which meets the ClinGen Pulmonary Hypertension VCEP pathogenicity threshold of >=0.75 (PP3 met, BP4 not met). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation data. Functional data was not available (BS3 and PS3 not evaluated). In summary, this variant meets the criteria to be classified as likely pathogenic (LP) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS1_moderate, PM1_strong, PM2_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024). -

Pulmonary hypertension, primary, 1 Pathogenic:1

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.7	H;H;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.9	D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.91		Gain of MoRF binding (P = 0.0836);Gain of MoRF binding (P = 0.0836);.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.31		Position offset: 48

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085307316; hg19: chr2-203397407;