rs1085307327

Positions:

• chr2-202532727-TCCCAG-CGGAGA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_001204.7(BMPR2):​c.1271_1276delinsCGGAGA​(p.Phe424_Gly426delinsSerGluArg) variant causes a missense, splice region 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).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMPR2 NM_001204.7 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.64

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001204.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BMPR2. . Gene score misZ 2.0624 (greater than the threshold 3.09). Trascript score misZ 3.2701 (greater than threshold 3.09). GenCC has associacion of gene with pulmonary hypertension, primary, 1, congenital heart disease, heritable pulmonary arterial hypertension, pulmonary arterial hypertension.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 2-202532727-TCCCAG-CGGAGA is Pathogenic according to our data. Variant chr2-202532727-TCCCAG-CGGAGA is described in ClinVar as [Pathogenic]. Clinvar id is 425909.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7	c.1271_1276delinsCGGAGA	p.Phe424_Gly426delinsSerGluArg	missense_variant, splice_region_variant	9/13	ENST00000374580.10
BMPR2	XM_011511687.2	c.1271_1276delinsCGGAGA	p.Phe424_Gly426delinsSerGluArg	missense_variant, splice_region_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.1271_1276delinsCGGAGA	p.Phe424_Gly426delinsSerGluArg	missense_variant, splice_region_variant	9/13	1	NM_001204.7	P1
BMPR2	ENST00000374574.2	c.1271_1276delinsCGGAGA	p.Phe424_Gly426delinsSerGluArg	missense_variant, splice_region_variant	9/12	2

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085307327; hg19: chr2-203397450;