rs2228545

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001204.7(BMPR2):c.2324G>A(p.Ser775Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0297 in 1,614,166 control chromosomes in the GnomAD database, including 849 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 54 hom., cov: 32)

Exomes 𝑓: 0.030 ( 795 hom. )

Consequence

BMPR2
NM_001204.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.05

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the BMPR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. Gene score misZ: 2.0624 (below the threshold of 3.09). Trascript score misZ: 3.2701 (above the threshold of 3.09). GenCC associations: The gene is linked to pulmonary hypertension, primary, 1, congenital heart disease, heritable pulmonary arterial hypertension, pulmonary arterial hypertension.

BP4

Computational evidence support a benign effect (MetaRNN=0.003867656).

BP6

Variant 2-202555989-G-A is Benign according to our data. Variant chr2-202555989-G-A is described in ClinVar as [Benign]. Clinvar id is 136528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-202555989-G-A is described in Lovd as [Benign]. Variant chr2-202555989-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0222 (3385/152278) while in subpopulation NFE AF= 0.0337 (2292/68022). AF 95% confidence interval is 0.0325. There are 54 homozygotes in gnomad4. There are 1584 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3385 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7 link	c.2324G>A	p.Ser775Asn	missense_variant	Exon 12 of 13	ENST00000374580.10	NP_001195.2	Q13873-1
BMPR2	XM_011511687.2 link	c.2324G>A	p.Ser775Asn	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 link	c.2324G>A	p.Ser775Asn	missense_variant	Exon 12 of 13	1	NM_001204.7	ENSP00000363708.4		Q13873-1
BMPR2	ENST00000374574.2 link	c.1586+3101G>A		intron_variant	Intron 11 of 11	2		ENSP00000363702.2		Q13873-2

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3387

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00627

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0239

Gnomad ASJ

AF:

0.0588

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00537

Gnomad FIN

AF:

0.0163

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0337

Gnomad OTH

AF:

0.0253

GnomAD3 exomes

AF:

0.0244

AC:

6145

AN:

251390

Hom.:

122

AF XY:

0.0247

AC XY:

3351

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.0138

Gnomad ASJ exome

AF:

0.0624

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00578

Gnomad FIN exome

AF:

0.0208

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0303

GnomAD4 exome

AF:

0.0305

AC:

44555

AN:

1461888

Hom.:

795

Cov.:

AF XY:

0.0298

AC XY:

21703

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00409

Gnomad4 AMR exome

AF:

0.0141

Gnomad4 ASJ exome

AF:

0.0634

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00669

Gnomad4 FIN exome

AF:

0.0225

Gnomad4 NFE exome

AF:

0.0346

Gnomad4 OTH exome

AF:

0.0279

GnomAD4 genome

AF:

0.0222

AC:

3385

AN:

152278

Hom.:

Cov.:

AF XY:

0.0213

AC XY:

1584

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00626

Gnomad4 AMR

AF:

0.0238

Gnomad4 ASJ

AF:

0.0588

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00538

Gnomad4 FIN

AF:

0.0163

Gnomad4 NFE

AF:

0.0337

Gnomad4 OTH

AF:

0.0251

Alfa

AF:

0.0327

Hom.:

171

Bravo

AF:

0.0223

TwinsUK

AF:

0.0372

AC:

138

ALSPAC

AF:

0.0350

AC:

135

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.0350

AC:

301

ExAC

AF:

0.0251

AC:

3049

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0316

EpiControl

AF:

0.0324

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Sep 03, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser775Asn in exon 12 of BMPR2: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (301/8600) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs2228545). In addition, serine (Ser) is not conserved in mammals or evolutionarily distant species and the change to asparagine (Asn) is present in 5 mammals. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary pulmonary hypertension

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pulmonary hypertension, primary, 1

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.0078

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.25

REVEL

Benign

0.28

Sift

Benign

0.70

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.014

MPC

0.31

ClinPred

0.015

GERP RS

4.8

Varity_R

0.11

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over