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GeneBe

4-849748-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_005255.4(GAK):c.3861C>T(p.His1287=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,613,302 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0042 ( 19 hom. )

Consequence

GAK
NM_005255.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0970
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 Benign. Variant got -11 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 4-849748-G-A is Benign according to our data. Variant chr4-849748-G-A is described in ClinVar as [Benign]. Clinvar id is 787170.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.097 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 445 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GAKNM_005255.4 linkuse as main transcriptc.3861C>T p.His1287= synonymous_variant 28/28 ENST00000314167.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GAKENST00000314167.9 linkuse as main transcriptc.3861C>T p.His1287= synonymous_variant 28/281 NM_005255.4 P1O14976-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00293
AC:
445
AN:
152128
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00248
Gnomad ASJ
AF:
0.00490
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00165
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00479
Gnomad OTH
AF:
0.00574
GnomAD3 exomes
AF:
0.00305
AC:
761
AN:
249136
Hom.:
3
AF XY:
0.00326
AC XY:
441
AN XY:
135094
show subpopulations
Gnomad AFR exome
AF:
0.000757
Gnomad AMR exome
AF:
0.00189
Gnomad ASJ exome
AF:
0.00440
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00318
Gnomad FIN exome
AF:
0.000233
Gnomad NFE exome
AF:
0.00456
Gnomad OTH exome
AF:
0.00378
GnomAD4 exome
AF:
0.00422
AC:
6171
AN:
1461056
Hom.:
19
Cov.:
32
AF XY:
0.00424
AC XY:
3083
AN XY:
726828
show subpopulations
Gnomad4 AFR exome
AF:
0.000807
Gnomad4 AMR exome
AF:
0.00231
Gnomad4 ASJ exome
AF:
0.00445
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00328
Gnomad4 FIN exome
AF:
0.000207
Gnomad4 NFE exome
AF:
0.00485
Gnomad4 OTH exome
AF:
0.00366
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00292
AC:
445
AN:
152246
Hom.:
1
Cov.:
33
AF XY:
0.00259
AC XY:
193
AN XY:
74430
show subpopulations
Gnomad4 AFR
AF:
0.000963
Gnomad4 AMR
AF:
0.00248
Gnomad4 ASJ
AF:
0.00490
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.00481
Gnomad4 OTH
AF:
0.00568
Alfa
AF:
0.00387
Hom.:
0
Bravo
AF:
0.00314
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00529
EpiControl
AF:
0.00546

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 submitterclinical testingInvitaeJun 20, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
Cadd
Benign
0.23
Dann
Benign
0.59

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.

Other links and lift over

dbSNP: rs55904229; hg19: chr4-843536; COSMIC: COSV100034246; COSMIC: COSV100034246; API