chr15-64204454-A-G

Position:

• chr15-64204454-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022048.5(CSNK1G1):​c.986T>C​(p.Val329Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V329I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CSNK1G1 NM_022048.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

CSNK1G1 (HGNC:2454): (casein kinase 1 gamma 1) This gene encodes a member of the casein kinase I gene family. This family is comprised of serine/threonine kinases that phosphorylate acidic proteins such as caseins. The encoded kinase plays a role in cell cycle checkpoint arrest in response to stalled replication forks by phosphorylating Claspin. A mutation in this gene may be associated with non-syndromic early-onset epilepsy (NSEOE). [provided by RefSeq, Jul 2016]

ENSG00000259316 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24879935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSNK1G1	NM_022048.5	c.986T>C	p.Val329Ala	missense_variant	9/12	ENST00000303052.13	NP_071331.2
CSNK1G1	NM_001329605.2	c.986T>C	p.Val329Ala	missense_variant	9/13		NP_001316534.1
CSNK1G1	NM_001329607.2	c.986T>C	p.Val329Ala	missense_variant	9/12		NP_001316536.1
CSNK1G1	NM_001329606.2	c.986T>C	p.Val329Ala	missense_variant	9/12		NP_001316535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSNK1G1	ENST00000303052.13	c.986T>C	p.Val329Ala	missense_variant	9/12	1	NM_022048.5	ENSP00000305777.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440996 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 716296

Gnomad4 AFR exome AF: 0.0000625

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

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

Aug 01, 2024

The c.986T>C (p.V329A) alteration is located in exon 9 (coding exon 8) of the CSNK1G1 gene. This alteration results from a T to C substitution at nucleotide position 986, causing the valine (V) at amino acid position 329 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	0.12
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.032	T;T;T;.;T;T;T;T;T;.;T
Eigen	Benign	0.093
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T;T;T;T;.;T;T;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.43	N;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.42	T;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.25	T;T;T;T;T;T;T;T;T;T;D
Polyphen		0.0	B;.;B;.;.;.;.;.;.;.;.
Vest4		0.57
MutPred		0.31		Gain of catalytic residue at V329 (P = 0.0118);Gain of catalytic residue at V329 (P = 0.0118);Gain of catalytic residue at V329 (P = 0.0118);Gain of catalytic residue at V329 (P = 0.0118);Gain of catalytic residue at V329 (P = 0.0118);Gain of catalytic residue at V329 (P = 0.0118);.;.;.;Gain of catalytic residue at V329 (P = 0.0118);.;
MVP		0.48
MPC		0.68
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs777666184; hg19: chr15-64496653;