chr2-202467566-T-C
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001204.7(BMPR2):āc.295T>Cā(p.Cys99Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ). 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 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR2 | NM_001204.7 | c.295T>C | p.Cys99Arg | missense_variant | 3/13 | ENST00000374580.10 | |
BMPR2 | XM_011511687.2 | c.295T>C | p.Cys99Arg | missense_variant | 3/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR2 | ENST00000374580.10 | c.295T>C | p.Cys99Arg | missense_variant | 3/13 | 1 | NM_001204.7 | P1 | |
BMPR2 | ENST00000374574.2 | c.295T>C | p.Cys99Arg | missense_variant | 3/12 | 2 | |||
BMPR2 | ENST00000479069.1 | n.202T>C | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2014 | p.Cys99Arg (TGT>CGT): c.295 T>C in exon 3 of the BMPR2 gene (NM_001204.6). The C99R mutation in the BMPR2 gene has been reported previously in several unrelated individuals with PAH (Machado R et al., 2006; Rosenzweig E et al., 2008; Machado R et al., 2009). C99R results in a nonconservative amino acid substitution at a position that is conserved across species. Mutations in nearby residues (C94R, E98K, T102A, S107P) have been reported in association with PAH, further supporting the functional importance of this region of the protein. Furthermore, the C99R mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, C99R in the BMPR2 gene is interpreted as a disease-causing mutation. This variant was found in PAH-ARRHYTHMIA - |
Primary pulmonary hypertension Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2022 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BMPR2 protein function. 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 determined to be pathogenic (PMID: 19555857, 30578397; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 212816). This missense change has been observed in individuals with pulmonary arterial hypertension (PMID: 16429395, 19555857; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 99 of the BMPR2 protein (p.Cys99Arg). - |
Pulmonary hypertension, primary, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Rare Disease Genomics Group, St George's University of London | - | - - |
Pulmonary arterial hypertension;C5679820:Idiopathic and/or familial pulmonary arterial hypertension Other:1
not provided, no classification provided | literature only | Wendy Chung Laboratory, Columbia University Medical Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at