chr2-208128252-G-GC
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_020989.4(CRYGC):c.475_476insG(p.Ala159GlyfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
CRYGC
NM_020989.4 frameshift
NM_020989.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.50
Genes affected
CRYGC (HGNC:2410): (crystallin gamma C) This gene encodes a member of the beta/gamma-crystallin family of proteins. Crystallins constitute the major proteins of vertebrate eye lens and maintain the transparency and refractive index of the lens. This gene and several family members are present in a gene cluster on chromosome 2. Mutations in this gene have been shown to cause multiple types of cataract, including Coppock-like cataract and zonular pulverulent cataract, among others. [provided by RefSeq, Jan 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.548 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-208128252-G-GC is Pathogenic according to our data. Variant chr2-208128252-G-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2856619.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYGC | NM_020989.4 | c.475_476insG | p.Ala159GlyfsTer5 | frameshift_variant | 3/3 | ENST00000282141.4 | |
LOC100507443 | NR_038437.1 | n.98-8798dup | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYGC | ENST00000282141.4 | c.475_476insG | p.Ala159GlyfsTer5 | frameshift_variant | 3/3 | 1 | NM_020989.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
CRYGC-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 30, 2023 | The CRYGC c.475dupG variant is predicted to result in a frameshift and premature protein termination (p.Ala159Glyfs*5). This variant occurs within the terminal exon of the CRYGC gene, near the stop codon. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At PreventionGenetics, we have detected this variant in another patient with childhood-onset cataracts (Internal Data). Frameshift variants in CRYGC are expected to be pathogenic and have been documented both up- and downstream of amino acid 159 in individuals with cataracts (Human Gene Mutation Database). This variant is interpreted as pathogenic. - |
Nuclear pulverulent cataract Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 15, 2023 | 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with CRYGC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala159Glyfs*5) in the CRYGC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the CRYGC protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.