Variant 4-849932-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005255.4(GAK):c.3794A>G(p.Lys1265Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0408 in 1,603,568 control chromosomes in the GnomAD database, including 1,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.035 ( 127 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1567 hom. )

Consequence

GAK
NM_005255.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.02

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]

GAK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004266292).

BP6

Variant 4-849932-T-C is Benign according to our data. Variant chr4-849932-T-C is described in ClinVar as [Benign]. Clinvar id is 1265262.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAK	NM_005255.4 linkuse as main transcript	c.3794A>G	p.Lys1265Arg	missense_variant	27/28	ENST00000314167.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAK	ENST00000314167.9 linkuse as main transcript	c.3794A>G	p.Lys1265Arg	missense_variant	27/28	1	NM_005255.4	P1	O14976-1

Frequencies

GnomAD3 genomes

AF:

0.0354

AC:

5278

AN:

149108

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0125

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.0424

Gnomad ASJ

AF:

0.0217

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.0363

Gnomad FIN

AF:

0.0496

Gnomad MID

AF:

0.0325

Gnomad NFE

AF:

0.0401

Gnomad OTH

AF:

0.0345

GnomAD3 exomes

AF:

0.0431

AC:

10570

AN:

245508

Hom.:

312

AF XY:

0.0438

AC XY:

5850

AN XY:

133542

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.0463

Gnomad ASJ exome

AF:

0.0229

Gnomad EAS exome

AF:

0.0994

Gnomad SAS exome

AF:

0.0392

Gnomad FIN exome

AF:

0.0489

Gnomad NFE exome

AF:

0.0393

Gnomad OTH exome

AF:

0.0398

GnomAD4 exome

AF:

0.0413

AC:

60067

AN:

1454352

Hom.:

1567

Cov.:

AF XY:

0.0414

AC XY:

29948

AN XY:

723376

show subpopulations

Gnomad4 AFR exome

AF:

0.00912

Gnomad4 AMR exome

AF:

0.0456

Gnomad4 ASJ exome

AF:

0.0217

Gnomad4 EAS exome

AF:

0.131

Gnomad4 SAS exome

AF:

0.0397

Gnomad4 FIN exome

AF:

0.0509

Gnomad4 NFE exome

AF:

0.0393

Gnomad4 OTH exome

AF:

0.0377

GnomAD4 genome

AF:

0.0354

AC:

5279

AN:

149216

Hom.:

127

Cov.:

AF XY:

0.0365

AC XY:

2653

AN XY:

72698

show subpopulations

Gnomad4 AFR

AF:

0.0125

Gnomad4 AMR

AF:

0.0424

Gnomad4 ASJ

AF:

0.0217

Gnomad4 EAS

AF:

0.103

Gnomad4 SAS

AF:

0.0361

Gnomad4 FIN

AF:

0.0496

Gnomad4 NFE

AF:

0.0402

Gnomad4 OTH

AF:

0.0342

Alfa

AF:

0.0406

Hom.:

236

Bravo

AF:

0.0343

TwinsUK

AF:

0.0421

AC:

156

ALSPAC

AF:

0.0433

AC:

167

ESP6500AA

AF:

0.00976

AC:

ESP6500EA

AF:

0.0380

AC:

327

ExAC

AF:

0.0424

AC:

5141

Asia WGS

AF:

0.0440

AC:

151

AN:

3478

EpiCase

AF:

0.0406

EpiControl

AF:

0.0431

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2021

This variant is associated with the following publications: (PMID: 26676575) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.38

T;.;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.0043

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

0.000054

P;P

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.4

N;N;.

REVEL

Benign

0.096

Sift

Benign

0.099

T;T;.

Sift4G

Uncertain

0.043

D;D;T

Polyphen

0.0050

B;.;.

Vest4

0.13

MPC

0.13

ClinPred

0.019

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.44

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over