2-202376511-A-AGGCGGCGGCGGC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001204.7(BMPR2):​c.-939_-928dupGGCGGCGGCGGC 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.012 (22 hom., cov: 16)
• Consequence: BMPR2 NM_001204.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67
• 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 -10 ACMG points.

• BP6: Variant 2-202376511-A-AGGCGGCGGCGGC is Benign according to our data. Variant chr2-202376511-A-AGGCGGCGGCGGC is described in ClinVar as [Benign]. Clinvar id is 2651825.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0116 (1461/125838) while in subpopulation NFE AF = 0.0144 (848/58908). AF 95% confidence interval is 0.0136. There are 22 homozygotes in GnomAd4. There are 713 alleles in the male GnomAd4 subpopulation. Median coverage is 16. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.-939_-928dupGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.-939_-928dupGGCGGCGGCGGC		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_-928dupGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 13	1	NM_001204.7	ENSP00000363708.4
ENSG00000273456	ENST00000724884.1	n.154+268_154+279dupGCCGCCGCCGCC		intron_variant	Intron 1 of 1
ENSG00000273456	ENST00000724885.1	n.106+110_106+121dupGCCGCCGCCGCC		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1458 AN: 125734 Hom.: 22 Cov.: 16

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00881

Gnomad ASJ AF: 0.00251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.00707

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

GnomAD4 genome AF: 0.0116 AC: 1461 AN: 125838 Hom.: 22 Cov.: 16 AF XY: 0.0118 AC XY: 713 AN XY: 60228

African (AFR) AF: 0.00400 AC: 136 AN: 34008

American (AMR) AF: 0.00880 AC: 104 AN: 11818

Ashkenazi Jewish (ASJ) AF: 0.00251 AC: 8 AN: 3186

East Asian (EAS) AF: 0.00 AC: 0 AN: 4174

South Asian (SAS) AF: 0.00408 AC: 12 AN: 2942

European-Finnish (FIN) AF: 0.0415 AC: 342 AN: 8242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.0144 AC: 848 AN: 58908

Other (OTH) AF: 0.00699 AC: 11 AN: 1574

Alfa AF: 0.00516 Hom.: 30

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ENSG00000289490: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

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;