10-100236957-G-C

Variant names:

• chr10-100236957-G-C
• NM_018294.6:c.1267C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018294.6(CWF19L1):​c.1267C>G​(p.Pro423Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CWF19L1 NM_018294.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CWF19L1	NM_018294.6	c.1267C>G	p.Pro423Ala	missense_variant	Exon 12 of 14	ENST00000354105.10	NP_060764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CWF19L1	ENST00000354105.10	c.1267C>G	p.Pro423Ala	missense_variant	Exon 12 of 14	1	NM_018294.6	ENSP00000326411.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1267C>G (p.P423A) alteration is located in exon 12 (coding exon 12) of the CWF19L1 gene. This alteration results from a C to G substitution at nucleotide position 1267, causing the proline (P) at amino acid position 423 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.017	D
Sift4G	Benign	0.22	T
Polyphen		0.96	D
Vest4		0.60
MutPred		0.80		Gain of catalytic residue at P423 (P = 0.1727);
MVP		0.63
MPC		0.55
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.25
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-101996714;