rs1085307197

chr2-202467522-G-Achr2-202467522-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001204.7(BMPR2):c.251G>A(p.Cys84Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C84F) has been classified as Pathogenic.

• 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

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 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001204.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-202467522-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 425744.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, BMPR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-202467522-G-A is Pathogenic according to our data. Variant chr2-202467522-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 812796.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7	c.251G>A	p.Cys84Tyr	missense_variant	3/13	ENST00000374580.10
BMPR2	XM_011511687.2	c.251G>A	p.Cys84Tyr	missense_variant	3/13

Ensembl

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