17-29250301-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_005208.5(CRYBA1):c.215+1G>T 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>T | splice_donor_variant, intron_variant | Intron 3 of 5 | 1 | NM_005208.5 | ENSP00000225387.3 | |||
CRYBA1 | ENST00000484605.1 | n.203+1G>T | 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
Cataract 10 multiple types Pathogenic:1
This sequence change affects a donor splice site in intron 3 of the CRYBA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with congenital bilateral cataracts in a family (PMID: 21850182). Two different variants affecting this nucleotide (c.215+1G>A and c.215+1G>C) have been determined to be pathogenic and segregate with cataracts in several families (PMID: 9788845, 22919269, 20142846, 26851658). In addition, experimental studies of the c.215+1G>A variant in have shown that changes to this CRYBA1 donor site result in exon skipping (PMID: 11006214). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at