rs1085307352

Positions:

• chr2-202552726-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4_Supporting PM2_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.1424C>A variant is a nonsense mutation in the kinase domain (exon 11 of 13). It is predicted to result in nonsense mediated mRNA decay, and therefore meets the criteria for PVS1. It is absent from gnomAD v2.1.1 (all samples), meeting PM2_supporting. There are three reports of this variant in the literature (PMIDs 16429395, 20534176 and 32581362). However, since PMID 16429395 summarized data from multiple countries, including the UK and French populations that were the subject of the later papers, it is not possible to determine if all three probands are independent. Thus conservatively, only counted 2 probands were counted (PS4_supporting). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, PS4_supporting (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350344424/MONDO:0015924/125

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BMPR2 NM_001204.7 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.91

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 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.1424C>A	p.Ser475*	stop_gained	11/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1424C>A	p.Ser475*	stop_gained	11/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1424C>A	p.Ser475*	stop_gained	11/13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1424C>A	p.Ser475*	stop_gained	11/12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461756 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:2

Pathogenic, reviewed by expert panel	curation	Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen	May 03, 2024	The BMPR2 c.1424C>A variant is a nonsense mutation in the kinase domain (exon 11 of 13). It is predicted to result in nonsense mediated mRNA decay, and therefore meets the criteria for PVS1. It is absent from gnomAD v2.1.1 (all samples), meeting PM2_supporting. There are three reports of this variant in the literature (PMIDs 16429395, 20534176 and 32581362). However, since PMID 16429395 summarized data from multiple countries, including the UK and French populations that were the subject of the later papers, it is not possible to determine if all three probands are independent. Thus conservatively, only counted 2 probands were counted (PS4_supporting). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, PS4_supporting (VCEP specification version 1.1, 1/18/2024). -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	-	- -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.93
GERP RS		5.6

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: rs1085307352; hg19: chr2-203417449;