rs755800734
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_031443.4(CCM2):c.55C>T(p.Arg19Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000248 in 1,614,006 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R19R) has been classified as Likely benign.
Frequency
Consequence
NM_031443.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCM2 | NM_031443.4 | c.55C>T | p.Arg19Ter | stop_gained | 2/10 | ENST00000258781.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCM2 | ENST00000258781.11 | c.55C>T | p.Arg19Ter | stop_gained | 2/10 | 1 | NM_031443.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251356Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135852
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461828Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727218
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74332
ClinVar
Submissions by phenotype
Cerebral cavernous malformation 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 29, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change creates a premature translational stop signal (p.Arg19*) in the CCM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCM2 are known to be pathogenic (PMID: 18300272, 24689081). This variant is present in population databases (rs755800734, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with cerebral cavernous malformations (PMID: 15122722, 23595507, 24466005). ClinVar contains an entry for this variant (Variation ID: 447028). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32170606, 27153162, 24466005, 27561926, 15122722, 19088124, 23595507, 19088123, 18300272, 30701383, 31254430, 27535533, 32615293, 36629374) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 02, 2017 | - - |
CCM2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 16, 2023 | The CCM2 c.55C>T variant is predicted to result in premature protein termination (p.Arg19*). This variant has been reported to be causative for cerebral cavernous malformations (CCMs) in multiple patients (Verlaan et al. 2004. Pub Med ID: 15122722; Stahl et al. 2008. PubMed ID: 18300272; Fusco et al. 2019. PubMed ID: 31254430). At PreventionGenetics, we have detected this variant in several families tested for CCM (Internal Data). Nonsense variants in CCM2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at