13-37104913-A-C

Position:

• chr13-37104913-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145203.6(CSNK1A1L):​c.344T>G​(p.Met115Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CSNK1A1L NM_145203.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.60

Genes affected

CSNK1A1L (HGNC:20289): (casein kinase 1 alpha 1 like) Predicted to enable protein serine/threonine kinase activity. Predicted to be involved in negative regulation of canonical Wnt signaling pathway and peptidyl-serine phosphorylation. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSNK1A1L	NM_145203.6	c.344T>G	p.Met115Arg	missense_variant	1/1	ENST00000379800.4	NP_660204.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSNK1A1L	ENST00000379800.4	c.344T>G	p.Met115Arg	missense_variant	1/1	6	NM_145203.6	ENSP00000369126.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.344T>G (p.M115R) alteration is located in exon 1 (coding exon 1) of the CSNK1A1L gene. This alteration results from a T to G substitution at nucleotide position 344, causing the methionine (M) at amino acid position 115 to be replaced by an arginine (R). 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	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.092
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0029	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.57		Gain of catalytic residue at Q119 (P = 0.0035);
MVP		0.96
MPC		0.89
ClinPred		0.99	D
GERP RS		-0.23
Varity_R		0.97
gMVP		0.34

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: rs183000285; hg19: chr13-37679050;