10-100233276-C-T

Position:

chr10-100233276-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_018294.6(CWF19L1):c.1568G>A(p.Arg523His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,613,552 control chromosomes in the GnomAD database, including 636 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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 0.022 ( 52 hom., cov: 32)

Exomes 𝑓: 0.027 ( 584 hom. )

Consequence

CWF19L1
NM_018294.6 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.762

Variant links:

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 links:

CHUK-DT (HGNC:55813): (CHUK divergent transcript)

CHUK-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026995838).

BP6

Variant 10-100233276-C-T is Benign according to our data. Variant chr10-100233276-C-T is described in ClinVar as [Benign]. Clinvar id is 3056968.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0217 (3304/152128) while in subpopulation NFE AF= 0.0316 (2148/68006). AF 95% confidence interval is 0.0305. There are 52 homozygotes in gnomad4. There are 1680 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CWF19L1	NM_018294.6 linkuse as main transcript	c.1568G>A	p.Arg523His	missense_variant	14/14	ENST00000354105.10	NP_060764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CWF19L1	ENST00000354105.10 linkuse as main transcript	c.1568G>A	p.Arg523His	missense_variant	14/14	1	NM_018294.6	ENSP00000326411	P1	Q69YN2-1
CHUK-DT	ENST00000667469.1 linkuse as main transcript	n.254C>T		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3307

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00500

Gnomad AMI

AF:

0.0927

Gnomad AMR

AF:

0.0167

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.0350

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0316

Gnomad OTH

AF:

0.0279

GnomAD3 exomes

AF:

0.0239

AC:

5956

AN:

248730

Hom.:

AF XY:

0.0252

AC XY:

3391

AN XY:

134646

show subpopulations

Gnomad AFR exome

AF:

0.00554

Gnomad AMR exome

AF:

0.0163

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0218

Gnomad FIN exome

AF:

0.0354

Gnomad NFE exome

AF:

0.0307

Gnomad OTH exome

AF:

0.0341

GnomAD4 exome

AF:

0.0266

AC:

38933

AN:

1461424

Hom.:

584

Cov.:

AF XY:

0.0269

AC XY:

19583

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.00484

Gnomad4 AMR exome

AF:

0.0176

Gnomad4 ASJ exome

AF:

0.0242

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0211

Gnomad4 FIN exome

AF:

0.0340

Gnomad4 NFE exome

AF:

0.0288

Gnomad4 OTH exome

AF:

0.0239

GnomAD4 genome

AF:

0.0217

AC:

3304

AN:

152128

Hom.:

Cov.:

AF XY:

0.0226

AC XY:

1680

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00499

Gnomad4 AMR

AF:

0.0167

Gnomad4 ASJ

AF:

0.0219

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0197

Gnomad4 FIN

AF:

0.0350

Gnomad4 NFE

AF:

0.0316

Gnomad4 OTH

AF:

0.0276

Alfa

AF:

0.0277

Hom.:

114

Bravo

AF:

0.0197

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0246

AC:

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0298

AC:

256

ExAC

AF:

0.0240

AC:

2918

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0306

EpiControl

AF:

0.0321

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 17

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

European Non-Finnish population allele frequency is 2.395% (rs35490714, 881/25114 alleles, 13 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

CWF19L1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 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

0.082

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0054

Eigen

Benign

0.037

Eigen_PC

Benign

0.040

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.68

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.0

REVEL

Benign

0.025

Sift

Benign

0.060

Sift4G

Uncertain

0.058

Polyphen

0.79

Vest4

0.086

MPC

0.22

ClinPred

0.016

GERP RS

4.5

Varity_R

0.11

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over