17-29250301-G-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_005208.5(CRYBA1):c.215+1G>C variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_005208.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CRYBA1 | ENST00000225387.8 | c.215+1G>C | splice_donor_variant, intron_variant | Intron 3 of 5 | 1 | NM_005208.5 | ENSP00000225387.3 | |||
CRYBA1 | ENST00000484605.1 | n.203+1G>C | splice_donor_variant, intron_variant | Intron 3 of 4 | 5 | ENSP00000464368.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 25
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
CRYBA1-related disorder Pathogenic:1
The CRYBA1 c.215+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant (also reported as 474G>C) was reported in individuals with autosomal dominant cataracts (Bateman et al. 2000. PubMed ID: 11006214). Different variants impacting this same nucleotide (c.215+1G>A, c.215+1G>T) have also been reported in individuals with autosomal dominant cataracts (Kannabiran et al. 1998. PubMed ID: 9788845; Ma et al. 2016. PubMed ID: 26851658; Yang et al. 2011. PubMed ID: 21850182). Functional studies support that variants disrupting this splice donor site result in skipping of exons 3 and 4 (Ma et al. 2016. PubMed ID: 26851658). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in CRYBA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Cataract 10 multiple types Pathogenic:1
Disruption of this splice site has been observed in individual(s) with early onset cataracts (PMID: 11006214, 9788845). It has also been observed to segregate with disease in related individuals. This variant is also known as 474G>C in the literature. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that disruption of this splice site results in in-frame skipping of exons 3 and 4, resulting in a truncated protein product (PMID: 26851658). For these reasons, this variant has been classified as Pathogenic. This sequence change falls in intron 3 of the CRYBA1 gene. It does not directly change the encoded amino acid sequence of the CRYBA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.