rs1085307162

chr2-202464823-G-Achr2-202464823-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP2

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a topological_domain Extracellular (size 123) in uniprot entity BMPR2_HUMAN there are 39 pathogenic changes around while only 10 benign (80%) in NM_001204.7
• PP2: Missense variant where missense usually causes diseases, BMPR2

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.91G>A	p.Glu31Lys	missense_variant	2/13	1	NM_001204.7	P1
BMPR2	ENST00000374574.2	c.91G>A	p.Glu31Lys	missense_variant	2/12	2
BMPR2	ENST00000479069.1			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

Not reported in ClinVar

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;.
MutationTaster	Benign	1.0	D;D
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;