rs1085307296

Positions:

• chr2-202530920-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001204.7(BMPR2):​c.1097delC​(p.Pro366fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BMPR2 NM_001204.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.363

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-202530920-GC-G is Pathogenic according to our data. Variant chr2-202530920-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 425871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.1097delC	p.Pro366fs	frameshift_variant	8/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1097delC	p.Pro366fs	frameshift_variant	8/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1097delC	p.Pro366fs	frameshift_variant	8/13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1097delC	p.Pro366fs	frameshift_variant	8/12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2015

Although the c.1097delC deletion in the BMPR2 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Proline 366, changing it to a Glutamine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Pro366GlnfsX9. This deletion is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the BMPR2 gene have been reported in HGMD in association with PAH (Stenson et al., 2014). Furthermore, the c.1097delC deletion was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.1097delC in the BMPR2 gene is interpreted as a pathogenic variant. -

Primary pulmonary hypertension Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 09, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BMPR2 are known to be pathogenic (PMID: 16429395). This variant has been observed in individual(s) with pulmonary arterial hypertension (PMID: 19555857). This variant is also known as c.1095delC, p.R365fsX8 in the literature. ClinVar contains an entry for this variant (Variation ID: 425871). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro366Glnfs*9) in the BMPR2 gene. It is expected to result in an absent or disrupted protein product. -

Pulmonary hypertension, primary, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

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- -

Computational scores

Source: dbNSFP v4.3

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: rs1085307296; hg19: chr2-203395643;