10-100233276-C-T

Variant names:

• chr10-100233276-C-T
• rs35490714
• NM_018294.6:c.1568G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (52 hom., cov: 32)
  • Exomes 𝑓: 0.027 (584 hom.)
• Consequence: CWF19L1 NM_018294.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.762

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]

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

ACMG classification

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 rank	MANE	Protein	UniProt
CWF19L1	NM_018294.6	c.1568G>A	p.Arg523His	missense_variant	Exon 14 of 14	ENST00000354105.10	NP_060764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CWF19L1	ENST00000354105.10	c.1568G>A	p.Arg523His	missense_variant	Exon 14 of 14	1	NM_018294.6	ENSP00000326411.6

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3307 AN: 152010 Hom.: 52 Cov.: 32

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.: 87 AF XY: 0.0252 AC XY: 3391 AN XY: 134646

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.: 32 AF XY: 0.0269 AC XY: 19583 AN XY: 727014

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.: 52 Cov.: 32 AF XY: 0.0226 AC XY: 1680 AN XY: 74356

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: 95

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0298 AC: 256

ExAC AF: 0.0240 AC: 2918

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0306

EpiControl AF: 0.0321

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 17 Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0054	T
Eigen	Benign	0.037
Eigen_PC	Benign	0.040
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.025
Sift	Benign	0.060	T
Sift4G	Uncertain	0.058	T
Polyphen		0.79	P
Vest4		0.086
MPC		0.22
ClinPred		0.016	T
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

Other links and lift over

dbSNP: rs35490714; hg19: chr10-101993033; COSMIC: COSV99059465; COSMIC: COSV99059465;