rs1085307244

Variant names:

• chr2-202514914-A-G
• rs1085307244
• NM_001204.7:c.556A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001204.7(BMPR2):​c.556A>G​(p.Met186Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.42
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary hypertension, primary, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-202514914-A-G is Pathogenic according to our data. Variant chr2-202514914-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 425805.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.556A>G	p.Met186Val	missense_variant	Exon 5 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.556A>G	p.Met186Val	missense_variant	Exon 5 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.556A>G	p.Met186Val	missense_variant	Exon 5 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.556A>G	p.Met186Val	missense_variant	Exon 5 of 12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary arterial hypertension associated with congenital heart disease Pathogenic:1

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.37	T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.7	L;L;.
PhyloP100		5.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.83	N;N;.
REVEL	Uncertain	0.46
Sift	Benign	0.36	T;T;.
Sift4G	Benign	0.46	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.25
MutPred		0.75		Loss of disorder (P = 0.0584);Loss of disorder (P = 0.0584);.;
MVP		0.96
MPC		0.33
ClinPred		0.42	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.64
Mutation Taster		=34/66	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1085307244; hg19: chr2-203379637;