chr12-64455936-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_013254.4(TBK1):ā€‹c.66T>Cā€‹(p.Asn22=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 1,613,322 control chromosomes in the GnomAD database, including 1,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.030 ( 116 hom., cov: 32)
Exomes š‘“: 0.044 ( 1616 hom. )

Consequence

TBK1
NM_013254.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.25
Variant links:
Genes affected
TBK1 (HGNC:11584): (TANK binding kinase 1) The NF-kappa-B (NFKB) complex of proteins is inhibited by I-kappa-B (IKB) proteins, which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the IKB proteins by IKB kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation and nuclear translocation of the NFKB complex. The protein encoded by this gene is similar to IKB kinases and can mediate NFKB activation in response to certain growth factors. The protein is also an important kinase for antiviral innate immunity response. [provided by RefSeq, Sep 2021]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.5).
BP6
Variant 12-64455936-T-C is Benign according to our data. Variant chr12-64455936-T-C is described in ClinVar as [Benign]. Clinvar id is 475941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64455936-T-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=2.25 with no splicing effect.
BA1
GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TBK1NM_013254.4 linkuse as main transcriptc.66T>C p.Asn22= synonymous_variant 2/21 ENST00000331710.10
TBK1XM_005268809.2 linkuse as main transcriptc.66T>C p.Asn22= synonymous_variant 2/21
TBK1XM_005268810.2 linkuse as main transcriptc.66T>C p.Asn22= synonymous_variant 2/21
TBK1XR_007063071.1 linkuse as main transcriptn.165T>C non_coding_transcript_exon_variant 2/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TBK1ENST00000331710.10 linkuse as main transcriptc.66T>C p.Asn22= synonymous_variant 2/211 NM_013254.4 P4

Frequencies

GnomAD3 genomes
AF:
0.0299
AC:
4551
AN:
152216
Hom.:
116
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00827
Gnomad AMI
AF:
0.0417
Gnomad AMR
AF:
0.0169
Gnomad ASJ
AF:
0.0265
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.0294
Gnomad FIN
AF:
0.0412
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.0469
Gnomad OTH
AF:
0.0205
GnomAD3 exomes
AF:
0.0324
AC:
8119
AN:
250762
Hom.:
197
AF XY:
0.0340
AC XY:
4602
AN XY:
135506
show subpopulations
Gnomad AFR exome
AF:
0.00683
Gnomad AMR exome
AF:
0.0165
Gnomad ASJ exome
AF:
0.0260
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.0315
Gnomad FIN exome
AF:
0.0382
Gnomad NFE exome
AF:
0.0460
Gnomad OTH exome
AF:
0.0283
GnomAD4 exome
AF:
0.0445
AC:
64951
AN:
1460988
Hom.:
1616
Cov.:
30
AF XY:
0.0447
AC XY:
32480
AN XY:
726770
show subpopulations
Gnomad4 AFR exome
AF:
0.00613
Gnomad4 AMR exome
AF:
0.0164
Gnomad4 ASJ exome
AF:
0.0267
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.0338
Gnomad4 FIN exome
AF:
0.0379
Gnomad4 NFE exome
AF:
0.0506
Gnomad4 OTH exome
AF:
0.0337
GnomAD4 genome
AF:
0.0299
AC:
4554
AN:
152334
Hom.:
116
Cov.:
32
AF XY:
0.0297
AC XY:
2211
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.00825
Gnomad4 AMR
AF:
0.0170
Gnomad4 ASJ
AF:
0.0265
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.0296
Gnomad4 FIN
AF:
0.0412
Gnomad4 NFE
AF:
0.0469
Gnomad4 OTH
AF:
0.0203
Alfa
AF:
0.0409
Hom.:
95
Bravo
AF:
0.0266
Asia WGS
AF:
0.0120
AC:
40
AN:
3478
EpiCase
AF:
0.0434
EpiControl
AF:
0.0405

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 28, 2019- -
Glaucoma 1, open angle, P Benign:1
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical CenterJul 20, 2016- -
Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.50
CADD
Benign
13
DANN
Benign
0.90
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs41292019; hg19: chr12-64849716; API