10-100238117-T-TC

Position:

• chr10-100238117-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018294.6(CWF19L1):​c.1158_1159insG​(p.Lys387GlufsTer3) 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CWF19L1 NM_018294.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.996

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-100238117-T-TC is Pathogenic according to our data. Variant chr10-100238117-T-TC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 813893.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CWF19L1	NM_018294.6	c.1158_1159insG	p.Lys387GlufsTer3	frameshift_variant	11/14	ENST00000354105.10	NP_060764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CWF19L1	ENST00000354105.10	c.1158_1159insG	p.Lys387GlufsTer3	frameshift_variant	11/14	1	NM_018294.6	ENSP00000326411	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 17 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Dec 03, 2018

The homozygous p.Lys387GlufsTer3 variant in CWF19L1 was identified by our study in one individual with Spinocerebellar Ataxia. The p.Lys387GlufsTer3 variant in CWF19L1 has not been previously reported in individuals with spinocerebellar ataxia and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 387 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. A knock-out zebrafish model for the CWF19L1 gene has a phenotype that matches spinocerebellar ataxia and at least two loss of function variants across multiple exons have been reported in association with spinocerebellar ataxiain the literature (PMID: 25361784, 27016154, 26197978). Loss of function of the CWF19L1 gene is a moderately established disease mechanism in autosomal recessive Spinocerebellar Ataxia. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1_Strong (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1589611043; hg19: chr10-101997874;