rs1085307197

Variant names:

• chr2-202467522-G-A
• rs1085307197
• NM_001204.7:c.251G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-202467522-G-A
• chr2-202467522-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS4_Moderate PM1_Strong PM5 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001204.7 (BMPR2):c.251G>A (p.Cys84Tyr)The BMPR2 c.251G>A variant is a missense variant predicted to cause a cysteine to tyrosine substitution at amino acid 84 (p.Cys84Tyr).The variant is absent from gnomAD controls v.2.1.1 and gnomAD v4.0.0 (PM2_supporting). Four unrelated pulmonary arterial hypertension probands were identified with this variant (PMID:31727138, PMID:29650961 and 2 identified in the internal ClinGen Pulmonary Hypertension VCEP database) (PS4_moderate). BMPR2 p.Cys84Tyr is located within the conserved extracellular domain and is a Cys residue critical for protein function (PMID:16429395, PMID:9886286) (PM1_strong). A different amino acid change at the same position (p.Cys84Phe) was classified as pathogenic (PMID:21737554, PMID:28507310) (PM5). Two more amino acid changes, p.Cys84Arg and p.Cys84Gly, were reported to be pathogenic (PMID:19555857). In silico prediction (REVEL =0.951) is consistent with a pathogenic effect for this variant (PP3). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_sup, PS4_mod, PM1_strong, PM5, PP3 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350399510/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 8.26
• Publications: 4 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS4: 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.
• PM5: 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.251G>A	p.Cys84Tyr	missense_variant	Exon 3 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.251G>A	p.Cys84Tyr	missense_variant	Exon 3 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.251G>A	p.Cys84Tyr	missense_variant	Exon 3 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.251G>A	p.Cys84Tyr	missense_variant	Exon 3 of 12	2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.158G>A		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:2

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 01, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_001204.7 (BMPR2):c.251G>A (p.Cys84Tyr) The BMPR2 c.251G>A variant is a missense variant predicted to cause a cysteine to tyrosine substitution at amino acid 84 (p.Cys84Tyr). The variant is absent from gnomAD controls v.2.1.1 and gnomAD v4.0.0 (PM2_supporting). Four unrelated pulmonary arterial hypertension probands were identified with this variant (PMID: 31727138, PMID: 29650961 and 2 identified in the internal ClinGen Pulmonary Hypertension VCEP database) (PS4_moderate). BMPR2 p.Cys84Tyr is located within the conserved extracellular domain and is a Cys residue critical for protein function (PMID: 16429395, PMID: 9886286) (PM1_strong). A different amino acid change at the same position (p.Cys84Phe) was classified as pathogenic (PMID: 21737554, PMID: 28507310) (PM5). Two more amino acid changes, p.Cys84Arg and p.Cys84Gly, were reported to be pathogenic (PMID: 19555857). In silico prediction (REVEL =0.951) is consistent with a pathogenic effect for this variant (PP3). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_sup, PS4_mod, PM1_strong, PM5, PP3 (VCEP specification version 1.1, 1/18/2024). -

Pulmonary arterial hypertension;C5679820:Idiopathic and/or familial pulmonary arterial hypertension Other:1

-

Wendy Chung Laboratory, Boston Children's Hospital

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	2.9	M;M;.
PhyloP100		8.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-10	D;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.97		Loss of catalytic residue at W85 (P = 0.046);Loss of catalytic residue at W85 (P = 0.046);.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1085307197; hg19: chr2-203332245;