chr10-100245798-C-T
Variant names:
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
Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000084 ( 0 hom. )
Consequence
CWF19L1
NM_018294.6 splice_donor, intron
NM_018294.6 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.36
Genes affected
CWF19L1 (HGNC:25613): (CWF19 like cell cycle control factor 1) This gene encodes a member of the CWF19 protein family. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia-17 and mild cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07111935 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.1, offset of -48, new splice context is: cagGTagag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-100245798-C-T is Pathogenic according to our data. Variant chr10-100245798-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 128882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100245798-C-T is described in Lovd as [Pathogenic].
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 0.0000657 AC: 10AN: 152180Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
10
AN:
152180
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000135 AC: 34AN: 251290Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135832
GnomAD3 exomes
AF:
AC:
34
AN:
251290
Hom.:
AF XY:
AC XY:
16
AN XY:
135832
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000838 AC: 122AN: 1455956Hom.: 0 Cov.: 28 AF XY: 0.0000731 AC XY: 53AN XY: 724726
GnomAD4 exome
AF:
AC:
122
AN:
1455956
Hom.:
Cov.:
28
AF XY:
AC XY:
53
AN XY:
724726
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000657 AC: 10AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74344
GnomAD4 genome
AF:
AC:
10
AN:
152180
Hom.:
Cov.:
33
AF XY:
AC XY:
6
AN XY:
74344
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
8
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 06, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 17, 2018 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2022 | 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) - |
Autosomal recessive spinocerebellar ataxia 17 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 02, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at