2-202376511-AGGCGGCGGCGGC-A

Variant names:

• chr2-202376511-AGGCGGCGGCGGC-A
• rs375624016
• NM_001204.7:c.-939_-928delGGCGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001204.7(BMPR2):​c.-939_-928delGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency: Genomes: 𝑓 0.0029 (2 hom., cov: 16)
• Consequence: BMPR2 NM_001204.7 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.43
• Publications: 3 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

ENSG00000273456 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-202376511-AGGCGGCGGCGGC-A is Benign according to our data. Variant chr2-202376511-AGGCGGCGGCGGC-A is described in ClinVar as [Likely_benign]. Clinvar id is 3049579.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00285 (359/125856) while in subpopulation AMR AF = 0.0077 (91/11818). AF 95% confidence interval is 0.00642. There are 2 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 16. This position passed quality control check.
• BS2: High AC in GnomAd4 at 359 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.-939_-928delGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.-939_-928delGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.-939_-928delGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 13	1	NM_001204.7	ENSP00000363708.4
ENSG00000273456	ENST00000724884.1	n.154+268_154+279delGCCGCCGCCGCC		intron_variant	Intron 1 of 1
ENSG00000273456	ENST00000724885.1	n.106+110_106+121delGCCGCCGCCGCC		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 358 AN: 125752 Hom.: 2 Cov.: 16

Gnomad AFR AF: 0.00274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00771

Gnomad ASJ AF: 0.00157

Gnomad EAS AF: 0.000716

Gnomad SAS AF: 0.00441

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00368

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00386

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

GnomAD4 genome AF: 0.00285 AC: 359 AN: 125856 Hom.: 2 Cov.: 16 AF XY: 0.00284 AC XY: 171 AN XY: 60236

African (AFR) AF: 0.00273 AC: 93 AN: 34012

American (AMR) AF: 0.00770 AC: 91 AN: 11818

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 5 AN: 3186

East Asian (EAS) AF: 0.000719 AC: 3 AN: 4174

South Asian (SAS) AF: 0.00476 AC: 14 AN: 2942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8248

Middle Eastern (MID) AF: 0.00385 AC: 1 AN: 260

European-Non Finnish (NFE) AF: 0.00248 AC: 146 AN: 58916

Other (OTH) AF: 0.00381 AC: 6 AN: 1574

Alfa AF: 0.00 Hom.: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BMPR2-related disorder Benign:1

Mar 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		3.4

Splicing

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

Other links and lift over

dbSNP: rs375624016; hg19: chr2-203241234;