rs2228545

Positions:

• chr2-202555989-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 6.05

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BMPR2
• 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/exons	MANE	UniProt
BMPR2	NM_001204.7	c.2324G>A	p.Ser775Asn	missense_variant	12/13	ENST00000374580.10
BMPR2	XM_011511687.2	c.2324G>A	p.Ser775Asn	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.2324G>A	p.Ser775Asn	missense_variant	12/13	1	NM_001204.7	P1
BMPR2	ENST00000374574.2	c.1586+3101G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3387 AN: 152160 Hom.: 54 Cov.: 32

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

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.: 32 AF XY: 0.0298 AC XY: 21703 AN XY: 727244

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.: 54 Cov.: 32 AF XY: 0.0213 AC XY: 1584 AN XY: 74452

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: 33

ESP6500EA AF: 0.0350 AC: 301

ExAC AF: 0.0251 AC: 3049

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0316

EpiControl AF: 0.0324

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 02, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Primary pulmonary hypertension Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Pulmonary hypertension, primary, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.0078
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.28
Sift	Benign	0.70	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.31
ClinPred		0.015	T
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

Other links and lift over

dbSNP: rs2228545; hg19: chr2-203420712;