rs1085307301

Positions:

• chr2-202530952-G-A
• chr2-202530952-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM1

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.1126G>A (p.Glu376Lys) variant is an exonic variant located 3 base pairs before the end of exon 8. The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_Supporting). The variant has not been reported in pulmonary arterial hypertension patients to date. The variant has been identified in a patient with progressive myositis ossificans and a patient with unknown phenotype (ClinVar ID 977222) (PS4_not met). The variant is located in the well-established kinase domain (PM1_met). However, protein and splice-site prediction algorithms do not predict pathogenicity ((REVEL score 0.47 (>0,25-<0.75); Splice AI score 0 (benign)) (PP3_not met, BP4_not met). PP1 was not evaluated due to absence of co-segregation data. No other missense variants at the same amino acid have been reported for PAH (PS1, PM5 not assessed). In summary, this variant meets the criteria to be classified as VUS for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350341606/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 ENST00000374580.10 missense, splice_region
• Scores: Splicing: ADA: 0.9361
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 9.93

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.1126G>A	p.Glu376Lys	missense_variant, splice_region_variant	8/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1126G>A	p.Glu376Lys	missense_variant, splice_region_variant	8/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1126G>A	p.Glu376Lys	missense_variant, splice_region_variant	8/13	1	NM_001204.7	ENSP00000363708	P1
BMPR2	ENST00000374574.2	c.1126G>A	p.Glu376Lys	missense_variant, splice_region_variant	8/12	2		ENSP00000363702

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Progressive myositis ossificans Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory of Genetic Skeletal Anomaly, Seoul National University Children's Hospital

-

- -

Pulmonary arterial hypertension Uncertain:1

Uncertain significance, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Sep 10, 2024

The BMPR2 c.1126G>A (p.Glu376Lys) variant is an exonic variant located 3 base pairs before the end of exon 8. The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_Supporting). The variant has not been reported in pulmonary arterial hypertension patients to date. The variant has been identified in a patient with progressive myositis ossificans and a patient with unknown phenotype (ClinVar ID 977222) (PS4_not met). The variant is located in the well-established kinase domain (PM1_met). However, protein and splice-site prediction algorithms do not predict pathogenicity ((REVEL score 0.47 (>0,25-<0.75); Splice AI score 0 (benign)) (PP3_not met, BP4_not met). PP1 was not evaluated due to absence of co-segregation data. No other missense variants at the same amino acid have been reported for PAH (PS1, PM5 not assessed). In summary, this variant meets the criteria to be classified as VUS for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2023

De novo variant with confirmed parentage in multiple patients referred for genetic testing at GeneDx; however, the reported clinical features are not consistent with the features typically observed in individuals with pathogenic variants in this gene and an expanded phenotype requires additional research; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.0	D;D;.
REVEL	Uncertain	0.47
Sift	Benign	0.036	D;D;.
Sift4G	Benign	0.068	T;T;.
Polyphen		0.22	B;.;.
Vest4		0.94
MutPred		0.73		Gain of methylation at E376 (P = 0.0198);Gain of methylation at E376 (P = 0.0198);.;
MVP		0.93
MPC		0.52
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.77
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.82
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: rs1085307301; hg19: chr2-203395675; COSMIC: COSV101001676;