5-123604724-G-T

Variant names:

• chr5-123604724-G-T
• rs1335600106
• NM_001364140.2:c.1186G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001364140.2(CSNK1G3):​c.1186G>T​(p.Val396Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,350 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CSNK1G3 NM_001364140.2 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

CSNK1G3 (HGNC:2456): (casein kinase 1 gamma 3) This gene encodes a member of a family of serine/threonine protein kinases that phosphorylate caseins and other acidic proteins. A related protein in the African clawed frog participates in the transmission of Wnt/beta-catenin signaling. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSNK1G3	NM_001364140.2	c.1186G>T	p.Val396Phe	missense_variant, splice_region_variant	Exon 12 of 14	ENST00000696905.1	NP_001351069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSNK1G3	ENST00000696905.1	c.1186G>T	p.Val396Phe	missense_variant, splice_region_variant	Exon 12 of 14		NM_001364140.2	ENSP00000512966.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246580 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133394

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454350 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723376

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

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

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1183G>T (p.V395F) alteration is located in exon 12 (coding exon 11) of the CSNK1G3 gene. This alteration results from a G to T substitution at nucleotide position 1183, causing the valine (V) at amino acid position 395 to be replaced by a phenylalanine (F). 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	0.90
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;.;.;.;.;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T;T;.;T;D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.0	.;.;.;.;.;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.020	D;D;D;D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D;D;D;D
Polyphen		0.0020	B;.;.;B;.;P;P
Vest4		0.72
MutPred		0.23		.;.;.;.;.;Loss of glycosylation at T399 (P = 0.1083);Loss of glycosylation at T399 (P = 0.1083);
MVP		0.58
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.87
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
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: rs1335600106; hg19: chr5-122940418;