chr2-202467522-G-A

Position:

• chr2-202467522-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5 PP3 PM2_Supporting PS4_Moderate PM1_Strong

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 ENST00000374580.10 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 8.26

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 Pathogenic. Variant got 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/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.251G>A	p.Cys84Tyr	missense_variant	3/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.251G>A	p.Cys84Tyr	missense_variant	3/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.251G>A	p.Cys84Tyr	missense_variant	3/13	1	NM_001204.7	ENSP00000363708	P1
BMPR2	ENST00000374574.2	c.251G>A	p.Cys84Tyr	missense_variant	3/12	2		ENSP00000363702
BMPR2	ENST00000479069.1	n.158G>A		non_coding_transcript_exon_variant	2/3	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

Pathogenic, reviewed by expert panel	curation	Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen	May 01, 2024	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). -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	-	- -

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

not provided, no classification provided

literature only

Wendy Chung Laboratory, Columbia University Medical Center

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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;.
MutationTaster	Benign	1.0	D;D
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

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

Other links and lift over

dbSNP: rs1085307197; hg19: chr2-203332245;