rs2270962

Positions:

• chr10-100256287-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_018294.6(CWF19L1):​c.479G>A​(p.Cys160Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,613,390 control chromosomes in the GnomAD database, including 16,440 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (6337 hom., cov: 32)
  • Exomes 𝑓: 0.089 (10103 hom.)
• Consequence: CWF19L1 NM_018294.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.55

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]

CWF19L1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 10-100256287-C-T is Benign according to our data. Variant chr10-100256287-C-T is described in ClinVar as [Benign]. Clinvar id is 128879.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CWF19L1	NM_018294.6	c.479G>A	p.Cys160Tyr	missense_variant	5/14	ENST00000354105.10	NP_060764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CWF19L1	ENST00000354105.10	c.479G>A	p.Cys160Tyr	missense_variant	5/14	1	NM_018294.6	ENSP00000326411.6

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32097 AN: 151974 Hom.: 6307 Cov.: 32

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0772

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.124 AC: 31163 AN: 251308 Hom.: 3517 AF XY: 0.116 AC XY: 15803 AN XY: 135862

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.0749

Gnomad EAS exome AF: 0.151

Gnomad SAS exome AF: 0.135

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0889 AC: 129947 AN: 1461296 Hom.: 10103 Cov.: 32 AF XY: 0.0885 AC XY: 64312 AN XY: 727002

Gnomad4 AFR exome AF: 0.541

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.0749

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.0652

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.212 AC: 32182 AN: 152094 Hom.: 6337 Cov.: 32 AF XY: 0.213 AC XY: 15821 AN XY: 74374

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0772

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.0688

Gnomad4 OTH AF: 0.186

Alfa AF: 0.0936 Hom.: 3495

Bravo AF: 0.226

TwinsUK AF: 0.0601 AC: 223

ALSPAC AF: 0.0618 AC: 238

ESP6500AA AF: 0.515 AC: 2270

ESP6500EA AF: 0.0662 AC: 569

ExAC AF: 0.130 AC: 15819

Asia WGS AF: 0.194 AC: 673 AN: 3478

EpiCase AF: 0.0679

EpiControl AF: 0.0690

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

CWF19L1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.00030	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.036	T;T
MetaRNN	Benign	0.00049	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.2	N;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.1	N;.
REVEL	Benign	0.042
Sift	Benign	0.27	T;.
Sift4G	Benign	0.12	T;.
Polyphen		0.0	B;.
Vest4		0.035
MPC		0.29
ClinPred		0.013	T
GERP RS		4.8
Varity_R		0.040
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs2270962; hg19: chr10-102016044; COSMIC: COSV62499069; COSMIC: COSV62499069;