rs41292027

Variant names:

• chr12-64501319-G-A
• rs41292027
• NM_013254.4:c.2139-11G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-64501319-G-A
• chr12-64501319-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013254.4(TBK1):​c.2139-11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,612,904 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (152 hom.)
• Consequence: TBK1 NM_013254.4 intron
• Scores: Splicing: ADA: 0.0005245
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.71
• Publications: 1 publications found

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]

TBK1 Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• autoinflammation with arthritis and vasculitis

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000288665 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 12-64501319-G-A is Benign according to our data. Variant chr12-64501319-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00816 (1241/152170) while in subpopulation AMR AF = 0.018 (275/15284). AF 95% confidence interval is 0.0162. There are 7 homozygotes in GnomAd4. There are 643 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBK1	NM_013254.4	c.2139-11G>A		intron_variant	Intron 20 of 20	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.2139-11G>A		intron_variant	Intron 20 of 20		XP_005268866.1
TBK1	XM_005268810.2	c.2139-11G>A		intron_variant	Intron 20 of 20		XP_005268867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.2139-11G>A		intron_variant	Intron 20 of 20	1	NM_013254.4	ENSP00000329967.5

Frequencies

GnomAD3 genomes AF: 0.00816 AC: 1241 AN: 152052 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00681

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00999

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.0136 AC: 3416 AN: 250568 AF XY: 0.0124

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00624

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0112 AC: 16319 AN: 1460734 Hom.: 152 Cov.: 30 AF XY: 0.0110 AC XY: 8013 AN XY: 726694

African (AFR) AF: 0.00138 AC: 46 AN: 33396

American (AMR) AF: 0.0400 AC: 1780 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00509 AC: 133 AN: 26112

East Asian (EAS) AF: 0.000858 AC: 34 AN: 39636

South Asian (SAS) AF: 0.0138 AC: 1191 AN: 86036

European-Finnish (FIN) AF: 0.00633 AC: 338 AN: 53388

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5766

European-Non Finnish (NFE) AF: 0.0110 AC: 12250 AN: 1111584

Other (OTH) AF: 0.00873 AC: 527 AN: 60342

GnomAD4 genome AF: 0.00816 AC: 1241 AN: 152170 Hom.: 7 Cov.: 32 AF XY: 0.00864 AC XY: 643 AN XY: 74392

African (AFR) AF: 0.00205 AC: 85 AN: 41518

American (AMR) AF: 0.0180 AC: 275 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4826

European-Finnish (FIN) AF: 0.00681 AC: 72 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00999 AC: 679 AN: 67992

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00848 Hom.: 4

Bravo AF: 0.00952

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 21, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00052
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41292027; hg19: chr12-64895099;