chr4-849932-T-C

Position:

• chr4-849932-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.02

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]

ACMG classification

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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	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	c.3794A>G	p.Lys1265Arg	missense_variant	27/28	1	NM_005255.4	P1

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5278 AN: 149108 Hom.: 126 Cov.: 32

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

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.: 35 AF XY: 0.0414 AC XY: 29948 AN XY: 723376

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.: 32 AF XY: 0.0365 AC XY: 2653 AN XY: 72698

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: 43

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.000054	P;P
PrimateAI	Uncertain	0.63	T
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	T
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

Other links and lift over

dbSNP: rs2306242; hg19: chr4-843720; COSMIC: COSV58504999; COSMIC: COSV58504999;