chr10-100245798-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_018294.6(CWF19L1):c.964+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000821 in 1,608,136 control chromosomes in the GnomAD database, with no homozygous occurrence. 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_018294.6 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CWF19L1 | NM_018294.6 | c.964+1G>A | splice_donor_variant, intron_variant | Intron 9 of 13 | ENST00000354105.10 | NP_060764.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152180Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000135 AC: 34AN: 251290Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135832
GnomAD4 exome AF: 0.0000838 AC: 122AN: 1455956Hom.: 0 Cov.: 28 AF XY: 0.0000731 AC XY: 53AN XY: 724726
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74344
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Published functional study demonstrated loss of protein product (Burns et al., 2014); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25361784) -
Functional studies have shown that this variant disrupts mRNA splicing and results in reduced mRNA levels in cells derived from affected individuals (PMID: 25361784). This sequence change affects a donor splice site in intron 9 of the CWF19L1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs587780326, ExAC 0.06%). This variant has been observed to segregate with spinocerebellar ataxia in a family (PMID: 25361784). ClinVar contains an entry for this variant (Variation ID: 128882). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CWF19L1 are known to be pathogenic (PMID: 25361784, 26197978, 27016154). For these reasons, this variant has been classified as Pathogenic. -
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Autosomal recessive spinocerebellar ataxia 17 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at