chr2-202376551-A-G

Position:

• chr2-202376551-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4 BA1 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The BMPR2 NM_001247.7 c.-924A>G variant is a 5' UTR variant with ClinVar variation ID: 897238 and allele ID: 883358. The highest population minor allele frequency in gnomAD v3.1.2 controls is 1.45% (115/7926 alleles, including 2 homozygotes) in the African/African American population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold of >1% for BA1, and therefore meets this stand-alone criterion (BA1). BS2_supporting was met based on the 2 observed homozygotes among gnomAD controls. BP4 was met based on the computational predictor, CADD, giving a score of 9.47 which is below the PH VCEP threshold of <=10.0. In summary, the variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BA1, BS2_supporting, BP4 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA539000938/MONDO:0015924/125

• Frequency: Genomes: 𝑓 0.0048 (2 hom., cov: 25)
• Consequence: BMPR2 NM_001204.7 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 0.0850

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 -10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7	c.-924A>G		5_prime_UTR_variant	1/13	ENST00000374580.10
BMPR2	XM_011511687.2	c.-924A>G		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.-924A>G		5_prime_UTR_variant	1/13	1	NM_001204.7	P1

Frequencies

GnomAD3 genomes AF: 0.00483 AC: 616 AN: 127506 Hom.: 2 Cov.: 25

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00312

Gnomad ASJ AF: 0.000315

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000231

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00695

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00484 AC: 617 AN: 127596 Hom.: 2 Cov.: 25 AF XY: 0.00479 AC XY: 294 AN XY: 61330

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.000315

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000231

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00686

Alfa AF: 0.00405 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary hypertension, primary, 1 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Pulmonary arterial hypertension Benign:1

Benign, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

May 03, 2024

The BMPR2 NM_001247.7 c.-924A>G variant is a 5' UTR variant with ClinVar variation ID: 897238 and allele ID: 883358. The highest population minor allele frequency in gnomAD v3.1.2 controls is 1.45% (115/7926 alleles, including 2 homozygotes) in the African/African American population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold of >1% for BA1, and therefore meets this stand-alone criterion (BA1). BS2_supporting was met based on the 2 observed homozygotes among gnomAD controls. BP4 was met based on the computational predictor, CADD, giving a score of 9.47 which is below the PH VCEP threshold of <=10.0. In summary, the variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BA1, BS2_supporting, BP4 (VCEP specification version 1.1, 1/18/2024). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.7
DANN	Benign	0.62

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1231549120; hg19: chr2-203241274;