chr2-202464823-G-A

Position:

• chr2-202464823-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001204.7(BMPR2):​c.91G>A​(p.Glu31Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,460,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.13

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 Likely_benign. Variant got -3 ACMG points.

• 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.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.91G>A	p.Glu31Lys	missense_variant	2/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.91G>A	p.Glu31Lys	missense_variant	2/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.91G>A	p.Glu31Lys	missense_variant	2/13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.91G>A	p.Glu31Lys	missense_variant	2/12	2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.-3G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460368 Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7 AN XY: 726252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2024

The p.E31K variant (also known as c.91G>A), located in coding exon 2 of the BMPR2 gene, results from a G to A substitution at nucleotide position 91. The glutamic acid at codon 31 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2023

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;.
Eigen	Benign	0.059
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	0.55	N;N;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0060	D;T;.
Sift4G	Benign	0.081	T;T;.
Polyphen		0.13	B;.;.
Vest4		0.73
MutPred		0.33		Gain of ubiquitination at E31 (P = 0.0267);Gain of ubiquitination at E31 (P = 0.0267);.;
MVP		0.97
MPC		0.38
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.44
gMVP		0.93

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: rs1085307162; hg19: chr2-203329546; COSMIC: COSV101001852; COSMIC: COSV101001852;