rs1085307189

Positions:

• chr2-202464978-AGGCAAGT-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001204.7(BMPR2) c.247+1_247+7del variant is a 7 bp deletion spanning the canonical donor splice site of intron 2. This variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). It is predicted to cause skipping of biologically relevant exon 2 (171 bp), resulting in an in-frame deletion of amino acids Ala26-Gln82 within the ligand-binding domain, that is predicted to escape nonsense-mediated decay (PVS1_strong). The predictions were recorded under PVS1 so PP3 was not applied to avoid double counting. Although the variant is predicted to cause a change in the length of the protein due to in-frame deletion, no functional data are available and thus PM4 is not applied. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PM2_supporting. (VCEP specifications version 1.1, 1/18/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA645294001/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 splice_donor, splice_region, intron
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 8.26

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.247+1_247+7delGCAAGTG		splice_donor_variant, splice_region_variant, intron_variant		ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.247+1_247+7delGCAAGTG		splice_donor_variant, splice_region_variant, intron_variant			XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.247+1_247+7delGCAAGTG		splice_donor_variant, splice_region_variant, intron_variant		1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.247+1_247+7delGCAAGTG		splice_donor_variant, splice_region_variant, intron_variant		2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.154+1_154+7delGCAAGTG		splice_donor_variant, splice_region_variant, intron_variant		3

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: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

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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Pulmonary arterial hypertension Uncertain:1

Uncertain significance, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

May 03, 2024

The NM_001204.7(BMPR2) c.247+1_247+7del variant is a 7 bp deletion spanning the canonical donor splice site of intron 2. This variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). It is predicted to cause skipping of biologically relevant exon 2 (171 bp), resulting in an in-frame deletion of amino acids Ala26-Gln82 within the ligand-binding domain, that is predicted to escape nonsense-mediated decay (PVS1_strong). The predictions were recorded under PVS1 so PP3 was not applied to avoid double counting. Although the variant is predicted to cause a change in the length of the protein due to in-frame deletion, no functional data are available and thus PM4 is not applied. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PM2_supporting. (VCEP specifications version 1.1, 1/18/2024) -

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: rs1085307189; hg19: chr2-203329701;