chr2-202464985-T-G

Position:

• chr2-202464985-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The BMPR2 c. 247+6T>G variant is an intronic variant which is located 6 base pairs upstream of the end of exon 2. Despite being located outside the canonical splice donor site, the variant was shown to lead to a partial loss of exon 2 (PubMed ID16728714). Two alternative splice sites were used. The first cryptic donor site was located 60 base pairs upstream and led to the loss of amino acids 63-82. The second cryptic splice site was located 108 base pairs upstream and led to the loss of amino acids 47-82. Both alternative transcripts resulted in a partial loss of the functionally critical extracellular domain of the BMPR2 receptor, which is located at amino acids 33-131 (PVS1). This variant is absent from gnomAD v4.1.0 and GnomAD v2.1.1 (controls) (PM2_supporting). This variant has two entries in ClinVar. One case was not counted as the affected status was “unknown.” The second patient was reported in Cogan et al (PubMed ID16728714) as an obligate carrier from a heritable pulmonary arterial hypertension family (1 known affected PAH proband, PS4 not met). PP1, PS2, PM6 were not assessed due to absence of co-segregation data. Of note, a variant at c.247+5G>A was reported to also result in the loss of the splice donor site and two alternative transcripts, one lacking p.47_82 and the second one missing p.63_82 (PMID:35346192). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA645294003/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 splice_donor_region, intron
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 1.92

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 9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7	c.247+6T>G		splice_donor_region_variant, intron_variant		ENST00000374580.10
BMPR2	XM_011511687.2	c.247+6T>G		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.247+6T>G		splice_donor_region_variant, intron_variant		1	NM_001204.7	P1
BMPR2	ENST00000374574.2	c.247+6T>G		splice_donor_region_variant, intron_variant		2
BMPR2	ENST00000479069.1	n.154+6T>G		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Sep 10, 2024

The BMPR2 c. 247+6T>G variant is an intronic variant which is located 6 base pairs upstream of the end of exon 2. Despite being located outside the canonical splice donor site, the variant was shown to lead to a partial loss of exon 2 (PubMed ID16728714). Two alternative splice sites were used. The first cryptic donor site was located 60 base pairs upstream and led to the loss of amino acids 63-82. The second cryptic splice site was located 108 base pairs upstream and led to the loss of amino acids 47-82. Both alternative transcripts resulted in a partial loss of the functionally critical extracellular domain of the BMPR2 receptor, which is located at amino acids 33-131 (PVS1). This variant is absent from gnomAD v4.1.0 and GnomAD v2.1.1 (controls) (PM2_supporting). This variant has two entries in ClinVar. One case was not counted as the affected status was “unknown.” The second patient was reported in Cogan et al (PubMed ID16728714) as an obligate carrier from a heritable pulmonary arterial hypertension family (1 known affected PAH proband, PS4 not met). PP1, PS2, PM6 were not assessed due to absence of co-segregation data. Of note, a variant at c.247+5G>A was reported to also result in the loss of the splice donor site and two alternative transcripts, one lacking p.47_82 and the second one missing p.63_82 (PMID: 35346192). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024). -

Pulmonary hypertension, primary, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

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

-

- -

Primary pulmonary hypertension Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 425733). This variant has been observed in individuals with pulmonary arterial hypertension (PMID: 16728714; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the BMPR2 gene. It does not directly change the encoded amino acid sequence of the BMPR2 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.0
DANN	Benign	0.79
FATHMM_MKL	Uncertain	0.78	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: -6

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085307191; hg19: chr2-203329708;