rs7073610

chr10-100246868-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_018294.6(CWF19L1):c.776C>T(p.Pro259Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.052 in 1,613,678 control chromosomes in the GnomAD database, including 2,439 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 Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.063 (350 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2089 hom.)
• Consequence: CWF19L1 NM_018294.6 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.56

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028273463).
• BP6: Variant 10-100246868-G-A is Benign according to our data. Variant chr10-100246868-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128881.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CWF19L1	NM_018294.6	c.776C>T	p.Pro259Leu	missense_variant	8/14	ENST00000354105.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CWF19L1	ENST00000354105.10	c.776C>T	p.Pro259Leu	missense_variant	8/14	1	NM_018294.6	P1

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9609 AN: 152058 Hom.: 350 Cov.: 33

Gnomad AFR AF: 0.0979

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0486

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.0555

Gnomad SAS AF: 0.0651

Gnomad FIN AF: 0.0556

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0472

Gnomad OTH AF: 0.0670

GnomAD3 exomes AF: 0.0516 AC: 12983 AN: 251384 Hom.: 380 AF XY: 0.0509 AC XY: 6920 AN XY: 135876

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.0559

Gnomad EAS exome AF: 0.0523

Gnomad SAS exome AF: 0.0617

Gnomad FIN exome AF: 0.0499

Gnomad NFE exome AF: 0.0440

Gnomad OTH exome AF: 0.0497

GnomAD4 exome AF: 0.0508 AC: 74267 AN: 1461502 Hom.: 2089 Cov.: 31 AF XY: 0.0506 AC XY: 36780 AN XY: 727064

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.0456

Gnomad4 ASJ exome AF: 0.0546

Gnomad4 EAS exome AF: 0.0647

Gnomad4 SAS exome AF: 0.0579

Gnomad4 FIN exome AF: 0.0518

Gnomad4 NFE exome AF: 0.0479

Gnomad4 OTH exome AF: 0.0582

GnomAD4 genome AF: 0.0632 AC: 9616 AN: 152176 Hom.: 350 Cov.: 33 AF XY: 0.0634 AC XY: 4714 AN XY: 74410

Gnomad4 AFR AF: 0.0977

Gnomad4 AMR AF: 0.0487

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.0558

Gnomad4 SAS AF: 0.0649

Gnomad4 FIN AF: 0.0556

Gnomad4 NFE AF: 0.0472

Gnomad4 OTH AF: 0.0664

Alfa AF: 0.0491 Hom.: 501

Bravo AF: 0.0643

TwinsUK AF: 0.0453 AC: 168

ALSPAC AF: 0.0467 AC: 180

ESP6500AA AF: 0.0953 AC: 420

ESP6500EA AF: 0.0463 AC: 398

ExAC AF: 0.0526 AC: 6388

Asia WGS AF: 0.0820 AC: 285 AN: 3478

EpiCase AF: 0.0440

EpiControl AF: 0.0436

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	22
Dann	Benign	0.94
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.046
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.00013	P;P
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.056
Sift	Benign	0.31	T
Sift4G	Benign	0.35	T
Polyphen		0.050	B
Vest4		0.087
MPC		0.18
ClinPred		0.031	T
GERP RS		4.6
Varity_R		0.083
gMVP		0.30

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: rs7073610; hg19: chr10-102006625; COSMIC: COSV62499001; COSMIC: COSV62499001;