rs886039222

Positions:

• chr2-202552771-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The ENST00000374580.10(BMPR2):​c.1469C>T​(p.Ala490Val) 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 ENST00000374580.10 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.91

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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000374580.10
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BMPR2. . Gene score misZ 2.0624 (greater than the threshold 3.09). Trascript score misZ 3.2701 (greater than threshold 3.09). GenCC has associacion of gene with pulmonary hypertension, primary, 1, congenital heart disease, heritable pulmonary arterial hypertension, pulmonary arterial hypertension.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 2-202552771-C-T is Pathogenic according to our data. Variant chr2-202552771-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 264653.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.1469C>T	p.Ala490Val	missense_variant	11/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1469C>T	p.Ala490Val	missense_variant	11/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1469C>T	p.Ala490Val	missense_variant	11/13	1	NM_001204.7	ENSP00000363708	P1
BMPR2	ENST00000374574.2	c.1469C>T	p.Ala490Val	missense_variant	11/12	2		ENSP00000363702

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary hypertension, primary, 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Center for Genomic Medicine, Kyoto University Graduate School of Medicine	Jul 11, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.017	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.91
MutPred		0.80		Gain of catalytic residue at A490 (P = 0.0173);Gain of catalytic residue at A490 (P = 0.0173);.;
MVP		0.89
MPC		1.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886039222; hg19: chr2-203417494;