rs1085308070
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_001204.7(BMPR2):c.296G>A(p.Cys99Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C99F) has been classified as Pathogenic.
Frequency
Consequence
NM_001204.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR2 | NM_001204.7 | c.296G>A | p.Cys99Tyr | missense_variant | 3/13 | ENST00000374580.10 | |
BMPR2 | XM_011511687.2 | c.296G>A | p.Cys99Tyr | missense_variant | 3/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR2 | ENST00000374580.10 | c.296G>A | p.Cys99Tyr | missense_variant | 3/13 | 1 | NM_001204.7 | P1 | |
BMPR2 | ENST00000374574.2 | c.296G>A | p.Cys99Tyr | missense_variant | 3/12 | 2 | |||
BMPR2 | ENST00000479069.1 | n.203G>A | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Primary pulmonary hypertension Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 11, 2019 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys99 amino acid residue in BMPR2. Other variant(s) that disrupt this residue have been observed in individuals with BMPR2-related conditions (PMID: 19555857, 29631995), which suggests that this may be a clinically significant amino acid residue. This variant has been observed in individuals affected with pulmonary artery hypertension (PMID: 19555857, 30578397, Invitae). ClinVar contains an entry for this variant (Variation ID: 425754). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 99 of the BMPR2 protein (p.Cys99Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. - |
Pulmonary hypertension, primary, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Rare Disease Genomics Group, St George's University of London | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at