10-100235713-T-C

Variant names:

• chr10-100235713-T-C
• rs560179736
• NM_018294.6:c.1426A>G

Variant summary

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

The NM_018294.6(CWF19L1):​c.1426A>G​(p.Lys476Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CWF19L1 NM_018294.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1426A>G	p.Lys476Glu	missense	Exon 13 of 14	NP_060764.3
	CWF19L1	NM_001303404.2		c.1306A>G	p.Lys436Glu	missense	Exon 12 of 13	NP_001290333.1
	CWF19L1	NM_001303405.2		c.1015A>G	p.Lys339Glu	missense	Exon 13 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.1426A>G	p.Lys476Glu	missense	Exon 13 of 14	ENSP00000326411.6	Q69YN2-1
	CWF19L1	ENST00000950162.1		c.1426A>G	p.Lys476Glu	missense	Exon 13 of 14	ENSP00000620221.1
	CWF19L1	ENST00000950161.1		c.1423A>G	p.Lys475Glu	missense	Exon 13 of 14	ENSP00000620220.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460234 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726488

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51928

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111908

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.023	D
Sift4G	Benign	0.13	T
Polyphen		0.99	D
Vest4		0.74
MutPred		0.58		Loss of methylation at K476 (P = 0.0148)
MVP		0.39
MPC		0.31
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.75
gMVP		0.77
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs560179736; hg19: chr10-101995470;