chr4-849710-G-A

Variant names:

• chr4-849710-G-A
• rs142107211
• NM_005255.4:c.3899C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005255.4(GAK):​c.3899C>T​(p.Ser1300Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000844 in 1,613,298 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00086 (5 hom.)
• Consequence: GAK NM_005255.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.35

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012696564).
• BP6: Variant 4-849710-G-A is Benign according to our data. Variant chr4-849710-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 720787.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAK	NM_005255.4	c.3899C>T	p.Ser1300Leu	missense_variant	Exon 28 of 28	ENST00000314167.9	NP_005246.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAK	ENST00000314167.9	c.3899C>T	p.Ser1300Leu	missense_variant	Exon 28 of 28	1	NM_005255.4	ENSP00000314499.4

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152158 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00406

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00127 AC: 317 AN: 249118 AF XY: 0.000963

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00502

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00409

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000471

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000863 AC: 1261 AN: 1461022 Hom.: 5 Cov.: 30 AF XY: 0.000831 AC XY: 604 AN XY: 726762

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33452

Gnomad4 AMR exome AF: 0.00417 AC: 186 AN: 44642

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26106

Gnomad4 EAS exome AF: 0.0138 AC: 548 AN: 39688

Gnomad4 SAS exome AF: 0.000360 AC: 31 AN: 86118

Gnomad4 FIN exome AF: 0.0000563 AC: 3 AN: 53278

Gnomad4 NFE exome AF: 0.000416 AC: 462 AN: 1111620

Gnomad4 Remaining exome AF: 0.000464 AC: 28 AN: 60350

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152276 Hom.: 0 Cov.: 34 AF XY: 0.000524 AC XY: 39 AN XY: 74448

Gnomad4 AFR AF: 0.000120 AC: 0.000120285 AN: 0.000120285

Gnomad4 AMR AF: 0.00176 AC: 0.00176309 AN: 0.00176309

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00407 AC: 0.00406977 AN: 0.00406977

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000676 AC: 0.000676451 AN: 0.000676451

Gnomad4 OTH AF: 0.000473 AC: 0.000473485 AN: 0.000473485

Alfa AF: 0.000824 Hom.: 1

Bravo AF: 0.000782

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000964 AC: 117

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000534

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.4	D;D;.
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.33
MVP		0.48
MPC		0.51
ClinPred		0.12	T
GERP RS		4.8
Varity_R		0.43
gMVP		0.27
Mutation Taster		=73/27	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

Publications

LitVar

Other links and lift over

dbSNP: rs142107211; hg19: chr4-843498; COSMIC: COSV58511634; COSMIC: COSV58511634;