rs375717897

Variant names:

• chr10-100233273-C-T
• rs375717897
• NM_018294.6:c.1571G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018294.6(CWF19L1):​c.1571G>A​(p.Arg524His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: CWF19L1 NM_018294.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57
• Publications: 4 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23055598).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CWF19L1	NM_018294.6	MANE Select	c.1571G>A	p.Arg524His	missense	Exon 14 of 14	NP_060764.3
	CWF19L1	NM_001303404.2		c.1451G>A	p.Arg484His	missense	Exon 13 of 13	NP_001290333.1
	CWF19L1	NM_001303405.2		c.1160G>A	p.Arg387His	missense	Exon 14 of 14	NP_001290334.1	Q69YN2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CWF19L1	ENST00000354105.10	TSL:1 MANE Select	c.1571G>A	p.Arg524His	missense	Exon 14 of 14	ENSP00000326411.6	Q69YN2-1
	CWF19L1	ENST00000950162.1		c.1571G>A	p.Arg524His	missense	Exon 14 of 14	ENSP00000620221.1
	CWF19L1	ENST00000950161.1		c.1568G>A	p.Arg523His	missense	Exon 14 of 14	ENSP00000620220.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151962 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248792 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461610 Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25 AN XY: 727110

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111854

Other (OTH) AF: 0.0000497 AC: 3 AN: 60376

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151962 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74198

African (AFR) AF: 0.0000484 AC: 2 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0030	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.070
Sift	Benign	0.060	T
Sift4G	Benign	0.064	T
Polyphen		0.94	P
Vest4		0.052
MVP		0.41
MPC		0.22
ClinPred		0.28	T
GERP RS		3.4
Varity_R		0.066
gMVP		0.35
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs375717897; hg19: chr10-101993030; COSMIC: COSV62499555; COSMIC: COSV62499555;