rs746530016

Variant names:

• chr5-123614379-A-G
• rs746530016
• NM_001364140.2:c.1354A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001364140.2(CSNK1G3):​c.1354A>G​(p.Ile452Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CSNK1G3 NM_001364140.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11
• Publications: 0 publications found

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]

CSNK1G3 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06077069).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364140.2. 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
	CSNK1G3	NM_001364140.2	MANE Select	c.1354A>G	p.Ile452Val	missense	Exon 14 of 14	NP_001351069.1	A0A8V8TKT3
	CSNK1G3	NM_001044723.3		c.1351A>G	p.Ile451Val	missense	Exon 14 of 14	NP_001038188.1
	CSNK1G3	NM_001437477.1		c.1348A>G	p.Ile450Val	missense	Exon 14 of 14	NP_001424406.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSNK1G3	ENST00000696905.1	MANE Select	c.1354A>G	p.Ile452Val	missense	Exon 14 of 14	ENSP00000512966.1	A0A8V8TKT3
	CSNK1G3	ENST00000345990.9	TSL:1	c.1351A>G	p.Ile451Val	missense	Exon 14 of 14	ENSP00000334735.5	Q9Y6M4-2
	CSNK1G3	ENST00000360683.6	TSL:1	c.1351A>G	p.Ile451Val	missense	Exon 13 of 13	ENSP00000353904.2	Q9Y6M4-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250408 AF XY: 0.00000739

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1461036 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726814

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111682

Other (OTH) AF: 0.00 AC: 0 AN: 60344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000102361), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.087
Sift	Benign	0.50	T
Sift4G	Benign	0.51	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.17		Loss of catalytic residue at I443 (P = 0.0631)
MVP		0.30
ClinPred		0.11	T
GERP RS		5.0
Varity_R		0.17
gMVP		0.057
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs746530016; hg19: chr5-122950073;