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GeneBe

4-851015-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005255.4(GAK):c.3578C>G(p.Ser1193Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GAK
NM_005255.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.13
Variant links:
Genes affected
GAK (HGNC:4113): (cyclin G associated kinase) In all eukaryotes, the cell cycle is governed by cyclin-dependent protein kinases (CDKs), whose activities are regulated by cyclins and CDK inhibitors in a diverse array of mechanisms that involve the control of phosphorylation and dephosphorylation of Ser, Thr or Tyr residues. Cyclins are molecules that possess a consensus domain called the 'cyclin box.' In mammalian cells, 9 cyclin species have been identified, and they are referred to as cyclins A through I. Cyclin G is a direct transcriptional target of the p53 tumor suppressor gene product and thus functions downstream of p53. GAK is an association partner of cyclin G and CDK5. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

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ACMG classification

Classification made for transcript

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=0.19811076).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GAKNM_005255.4 linkuse as main transcriptc.3578C>G p.Ser1193Cys missense_variant 26/28 ENST00000314167.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GAKENST00000314167.9 linkuse as main transcriptc.3578C>G p.Ser1193Cys missense_variant 26/281 NM_005255.4 P1O14976-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251478
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461792
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727200
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
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.:
33
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 29, 2023The c.3578C>G (p.S1193C) alteration is located in exon 26 (coding exon 26) of the GAK gene. This alteration results from a C to G substitution at nucleotide position 3578, causing the serine (S) at amino acid position 1193 to be replaced by a cysteine (C). 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
0.084
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.39
Cadd
Benign
23
Dann
Uncertain
0.99
DEOGEN2
Benign
0.39
T;.;T
Eigen
Uncertain
0.25
Eigen_PC
Benign
0.22
FATHMM_MKL
Benign
0.47
N
LIST_S2
Benign
0.81
T;T;D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.20
T;T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Uncertain
2.5
M;.;.
MutationTaster
Benign
0.89
N;N
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-2.8
D;D;.
REVEL
Benign
0.069
Sift
Uncertain
0.015
D;D;.
Sift4G
Uncertain
0.028
D;D;D
Polyphen
0.95
P;.;.
Vest4
0.27
MutPred
0.23
Gain of glycosylation at S1193 (P = 0.0035);.;.;
MVP
0.32
MPC
0.39
ClinPred
0.80
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.15
gMVP
0.12

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs768579483; hg19: chr4-844803; API