rs863223426

Positions:

• chr2-202467648-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001204.7(BMPR2):​c.377A>G​(p.Asn126Ser) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.71

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity BMPR2_HUMAN
• 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, 0.867
• PP5: Variant 2-202467648-A-G is Pathogenic according to our data. Variant chr2-202467648-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.377A>G	p.Asn126Ser	missense_variant	3/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.377A>G	p.Asn126Ser	missense_variant	3/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.377A>G	p.Asn126Ser	missense_variant	3/13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.377A>G	p.Asn126Ser	missense_variant	3/12	2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.284A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 03, 2014

p.Asn126Ser (AAC>AGC): c.377 A>G in exon 3 of the BMPR2 gene (NM_001204.6). The N126S mutation in the BMPR2 gene has been reported previously in three unrelated individuals with a diagnosis of PAH (Machado R et al., 2009; Girerd B et al., 2010). This substitution occurs at a position that is completely conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Mutations in nearby residues (C118Y, C118W, C123S, C123R, N124D) have been reported in association with PAH, further supporting the functional importance of this region of the protein. Furthermore, the N126S mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, N126S in the BMPR2 gene is interpreted as a disease-causing mutation. This variant was found in PAH-ARRHYTHMIA -

Primary pulmonary hypertension Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BMPR2 protein function. ClinVar contains an entry for this variant (Variation ID: 212817). This missense change has been observed in individuals with pulmonary arterial hypertension (PMID: 19555857, 20534176, 21737554, 29843651, 31727138, 32581362). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 126 of the BMPR2 protein (p.Asn126Ser). -

Pulmonary hypertension, primary, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

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- -

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

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D;D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.014	D;D;.
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.88
MutPred		0.62		Loss of catalytic residue at N126 (P = 0.039);Loss of catalytic residue at N126 (P = 0.039);.;
MVP		0.95
MPC		0.96
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.85
gMVP		0.68

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: rs863223426; hg19: chr2-203332371; COSMIC: COSV101001618;