rs112862820

chr2-202464818-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS2

The NM_001204.7(BMPR2):c.86A>G(p.Asn29Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000414 in 1,612,138 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.62

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in NM_001204.7
• PP2: Missense variant where missense usually causes diseases, BMPR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0071210563).
• BP6: Variant 2-202464818-A-G is Benign according to our data. Variant chr2-202464818-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 333638.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=1}.
• BS2: High AC in GnomAd at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7	c.86A>G	p.Asn29Ser	missense_variant	2/13	ENST00000374580.10
BMPR2	XM_011511687.2	c.86A>G	p.Asn29Ser	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.86A>G	p.Asn29Ser	missense_variant	2/13	1	NM_001204.7	P1
BMPR2	ENST00000374574.2	c.86A>G	p.Asn29Ser	missense_variant	2/12	2
BMPR2	ENST00000479069.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00770

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000512 AC: 128 AN: 250020 Hom.: 0 AF XY: 0.000408 AC XY: 55 AN XY: 134964

Gnomad AFR exome AF: 0.00696

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000221 AC: 322 AN: 1459840 Hom.: 1 Cov.: 31 AF XY: 0.000208 AC XY: 151 AN XY: 725904

Gnomad4 AFR exome AF: 0.00748

Gnomad4 AMR exome AF: 0.000315

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00248 AC XY: 185 AN XY: 74474

Gnomad4 AFR AF: 0.00782

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000381 Hom.: 0

Bravo AF: 0.00229

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000593 AC: 72

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The p.N29S variant (also known as c.86A>G), located in coding exon 2 of the BMPR2 gene, results from an A to G substitution at nucleotide position 86. The asparagine at codon 29 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Primary pulmonary hypertension Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

- -

Pulmonary hypertension, primary, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

BMPR2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Benign	0.92
DEOGEN2	Benign	0.32	T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.85	T;T;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0071	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.61	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.30	N;N;.
REVEL	Benign	0.28
Sift	Benign	1.0	T;T;.
Sift4G	Benign	0.83	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.13
MVP		0.64
MPC		0.26
ClinPred		0.027	T
GERP RS		4.2
Varity_R		0.025
gMVP		0.27

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: rs112862820; hg19: chr2-203329541;