2-202552837-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001204.7(BMPR2):​c.1535A>G​(p.Lys512Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

BMPR2
NM_001204.7 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.38
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the BMPR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. Gene score misZ: 2.0624 (below the threshold of 3.09). Trascript score misZ: 3.2701 (above the threshold of 3.09). GenCC associations: The gene is linked to pulmonary hypertension, primary, 1, congenital heart disease, heritable pulmonary arterial hypertension, pulmonary arterial hypertension.
BP4
Computational evidence support a benign effect (MetaRNN=0.24380562).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BMPR2NM_001204.7 linkc.1535A>G p.Lys512Arg missense_variant Exon 11 of 13 ENST00000374580.10 NP_001195.2 Q13873-1
BMPR2XM_011511687.2 linkc.1535A>G p.Lys512Arg missense_variant Exon 11 of 13 XP_011509989.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BMPR2ENST00000374580.10 linkc.1535A>G p.Lys512Arg missense_variant Exon 11 of 13 1 NM_001204.7 ENSP00000363708.4 Q13873-1
BMPR2ENST00000374574.2 linkc.1535A>G p.Lys512Arg missense_variant Exon 11 of 12 2 ENSP00000363702.2 Q13873-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Dec 18, 2019
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The BMPR2 c.1535A>G; p.Lys512Arg variant, to our knowledge, is not reported in the medical literature or gene-specific databases. The variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. However, another variant in the same codon, p.Lys512Thr, is reported in one family with pulmonary arterial hypertension and transfected expressed protein mislocalizes in cells (John 2015, Machado 2001). The lysine at codon 512 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Lys512Arg variant is uncertain at this time. References: John A et al. Defective cellular trafficking of the bone morphogenetic protein receptor type II by mutations underlying familial pulmonary arterial hypertension. Gene. 2015 Apr 25;561(1):148-56. Machado RD et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet. 2001 Jan;68(1):92-102. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
0.0096
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
T;.;.
Eigen
Benign
-0.10
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.24
T;T;T
MetaSVM
Benign
-0.39
T
MutationAssessor
Benign
0.55
N;N;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-0.85
N;N;.
REVEL
Benign
0.24
Sift
Benign
0.18
T;T;.
Sift4G
Benign
0.30
T;T;.
Polyphen
0.0010
B;.;.
Vest4
0.31
MutPred
0.36
Loss of ubiquitination at K512 (P = 0.0041);Loss of ubiquitination at K512 (P = 0.0041);.;
MVP
0.77
MPC
0.27
ClinPred
0.82
D
GERP RS
5.5
Varity_R
0.31
gMVP
0.53

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1085307364; hg19: chr2-203417560; API