Genetic Variant NM_018294.6:c.1568G>A (chr10-100233276-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

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

Publications

11 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 52 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018294.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CWF19L1	NM_018294.6	MANE Select	c.1568G>A	p.Arg523His	missense	Exon 14 of 14	NP_060764.3
CWF19L1	NM_001303404.2		c.1448G>A	p.Arg483His	missense	Exon 13 of 13	NP_001290333.1
CWF19L1	NM_001303405.2		c.1157G>A	p.Arg386His	missense	Exon 14 of 14	NP_001290334.1	Q69YN2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CWF19L1	ENST00000354105.10	TSL:1 MANE Select	c.1568G>A	p.Arg523His	missense	Exon 14 of 14	ENSP00000326411.6	Q69YN2-1
CWF19L1	ENST00000950162.1		c.1568G>A	p.Arg523His	missense	Exon 14 of 14	ENSP00000620221.1
CWF19L1	ENST00000950161.1		c.1565G>A	p.Arg522His	missense	Exon 14 of 14	ENSP00000620220.1

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

GnomAD2 exomes

AF:

0.0239

AC:

5956

AN:

248730

AF XY:

0.0252

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 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

African (AFR)

AF:

0.00484

AC:

162

AN:

33472

American (AMR)

AF:

0.0176

AC:

787

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

632

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.0211

AC:

1818

AN:

86166

European-Finnish (FIN)

AF:

0.0340

AC:

1814

AN:

53408

Middle Eastern (MID)

AF:

0.0432

AC:

249

AN:

5766

European-Non Finnish (NFE)

AF:

0.0288

AC:

32023

AN:

1111718

Other (OTH)

AF:

0.0239

AC:

1445

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

1940

3880

5819

7759

9699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1144

2288

3432

4576

5720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0217

AC:

3304

AN:

152128

Hom.:

Cov.:

AF XY:

0.0226

AC XY:

1680

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00499

AC:

207

AN:

41490

American (AMR)

AF:

0.0167

AC:

255

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.0197

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0350

AC:

370

AN:

10576

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0316

AC:

2148

AN:

68006

Other (OTH)

AF:

0.0276

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

167

334

500

667

834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0267

Hom.:

239

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive spinocerebellar ataxia 17 (1)

CWF19L1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

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

PhyloP100

0.76

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

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over