10-100235671-CAA-C

Position:

• chr10-100235671-CAA-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_018294.6(CWF19L1):​c.1466_1467del​(p.Phe489TrpfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CWF19L1 NM_018294.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.54

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0934 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-100235671-CAA-C is Pathogenic according to our data. Variant chr10-100235671-CAA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504148.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CWF19L1	NM_018294.6	c.1466_1467del	p.Phe489TrpfsTer8	frameshift_variant	13/14	ENST00000354105.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CWF19L1	ENST00000354105.10	c.1466_1467del	p.Phe489TrpfsTer8	frameshift_variant	13/14	1	NM_018294.6	P1
CWF19L1	ENST00000478047.1	n.1621_1622del		non_coding_transcript_exon_variant	4/5	2
CWF19L1	ENST00000468709.5	c.*1016_*1017del		3_prime_UTR_variant, NMD_transcript_variant	12/13	2
CWF19L1	ENST00000482452.5	c.*853_*854del		3_prime_UTR_variant, NMD_transcript_variant	11/13	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455922 Hom.: 0 AF XY: 0.00000414 AC XY: 3 AN XY: 724732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2018

The c.1466_1467delTT variant in the CWF19L1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1466_1467delTT variant causes a frameshift starting with codon Phenylalanine 489, changes this amino acid to a Tryptophan residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Phe489TrpfsX8. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 50 amino acids are replaced with 7 incorrect amino acids. Furthermore, the c.1466_1467delTT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1466_1467delTT as a likely pathogenic variant. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2022

Not expected to trigger nonsense-mediated mRNA decay Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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: rs1389916079; hg19: chr10-101995428;