rs1085307249

Variant names:

• chr2-202518864-TT-AAGG
• rs1085307249
• NM_001204.7:c.664_665delTTinsAAGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP2 PP5

The NM_001204.7(BMPR2):​c.664_665delTTinsAAGG​(p.Leu222LysfsTer9) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 frameshift, missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.96

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 12 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
• PP2: Missense variant in the BMPR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. Gene score misZ: 2.0624 (below the threshold of 3.09). Trascript score misZ: 3.2701 (above the threshold of 3.09). GenCC associations: The gene is linked to pulmonary hypertension, primary, 1, congenital heart disease, heritable pulmonary arterial hypertension, pulmonary arterial hypertension.
• PP5: Variant 2-202518864-TT-AAGG is Pathogenic according to our data. Variant chr2-202518864-TT-AAGG is described in ClinVar as [Pathogenic]. Clinvar id is 425812.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.664_665delTTinsAAGG	p.Leu222LysfsTer9	frameshift_variant, missense_variant	Exon 6 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.664_665delTTinsAAGG	p.Leu222LysfsTer9	frameshift_variant, missense_variant	Exon 6 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.664_665delTTinsAAGG	p.Leu222LysfsTer9	frameshift_variant, missense_variant	Exon 6 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.664_665delTTinsAAGG	p.Leu222LysfsTer9	frameshift_variant, missense_variant	Exon 6 of 12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary hypertension, primary, 1 Pathogenic:1

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085307249; hg19: chr2-203383587;