rs758990535

Variant names:

• chr2-202555961-A-G
• rs758990535
• NM_001204.7:c.2296A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001204.7(BMPR2):​c.2296A>G​(p.Thr766Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T766T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 4.93
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15699977).
• BP6: Variant 2-202555961-A-G is Benign according to our data. Variant chr2-202555961-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 425978.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.2296A>G	p.Thr766Ala	missense_variant	Exon 12 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.2296A>G	p.Thr766Ala	missense_variant	Exon 12 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.2296A>G	p.Thr766Ala	missense_variant	Exon 12 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1586+3073A>G		intron_variant	Intron 11 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251238 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary hypertension, primary, 1 Uncertain:1

-

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Primary pulmonary hypertension Benign:1

Nov 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.23
Sift	Benign	0.42	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.093
MutPred		0.14		Loss of glycosylation at T766 (P = 0.0254);
MVP		0.82
MPC		0.32
ClinPred		0.20	T
GERP RS		4.6
Varity_R		0.045
gMVP		0.24
Mutation Taster		=88/12	polymorphism

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: rs758990535; hg19: chr2-203420684;