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GeneBe

4-849718-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_005255.4(GAK):c.3891C>T(p.Asp1297=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,613,412 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.011 ( 39 hom., cov: 33)
Exomes 𝑓: 0.0026 ( 26 hom. )

Consequence

GAK
NM_005255.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.21
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 -15 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=-0.63).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 4-849718-G-A is Benign according to our data. Variant chr4-849718-G-A is described in ClinVar as [Benign]. Clinvar id is 778842.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=1.21 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1734/152274) while in subpopulation AFR AF= 0.0352 (1465/41572). AF 95% confidence interval is 0.0337. There are 39 homozygotes in gnomad4. There are 803 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
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 1733 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GAKNM_005255.4 linkuse as main transcriptc.3891C>T p.Asp1297= synonymous_variant 28/28 ENST00000314167.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GAKENST00000314167.9 linkuse as main transcriptc.3891C>T p.Asp1297= synonymous_variant 28/281 NM_005255.4 P1O14976-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0114
AC:
1733
AN:
152156
Hom.:
39
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0353
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00863
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00163
Gnomad OTH
AF:
0.00908
GnomAD3 exomes
AF:
0.00393
AC:
980
AN:
249490
Hom.:
11
AF XY:
0.00320
AC XY:
432
AN XY:
135178
show subpopulations
Gnomad AFR exome
AF:
0.0376
Gnomad AMR exome
AF:
0.00308
Gnomad ASJ exome
AF:
0.000898
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000984
Gnomad FIN exome
AF:
0.000232
Gnomad NFE exome
AF:
0.00220
Gnomad OTH exome
AF:
0.00230
GnomAD4 exome
AF:
0.00262
AC:
3833
AN:
1461138
Hom.:
26
Cov.:
30
AF XY:
0.00240
AC XY:
1744
AN XY:
726844
show subpopulations
Gnomad4 AFR exome
AF:
0.0370
Gnomad4 AMR exome
AF:
0.00307
Gnomad4 ASJ exome
AF:
0.00126
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.000282
Gnomad4 NFE exome
AF:
0.00193
Gnomad4 OTH exome
AF:
0.00376
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0114
AC:
1734
AN:
152274
Hom.:
39
Cov.:
33
AF XY:
0.0108
AC XY:
803
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.0352
Gnomad4 AMR
AF:
0.00862
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.00163
Gnomad4 OTH
AF:
0.00899
Alfa
AF:
0.00585
Hom.:
8
Bravo
AF:
0.0125
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.00218
EpiControl
AF:
0.00267

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 testingInvitaeJul 06, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.63
Cadd
Benign
5.9
Dann
Benign
0.62

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: rs7693026; hg19: chr4-843506; API