chr12-64501319-G-A

Position:

• chr12-64501319-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 403523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64501319-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1241 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBK1	NM_013254.4	c.2139-11G>A		intron_variant		ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.2139-11G>A		intron_variant			XP_005268866.1
TBK1	XM_005268810.2	c.2139-11G>A		intron_variant			XP_005268867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.2139-11G>A		intron_variant		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

GnomAD3 exomes AF: 0.0136 AC: 3416 AN: 250568 Hom.: 49 AF XY: 0.0124 AC XY: 1674 AN XY: 135434

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 SAS exome AF: 0.0144

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

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.0400

Gnomad4 ASJ exome AF: 0.00509

Gnomad4 EAS exome AF: 0.000858

Gnomad4 SAS exome AF: 0.0138

Gnomad4 FIN exome AF: 0.00633

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00873

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

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.00681

Gnomad4 NFE AF: 0.00999

Gnomad4 OTH AF: 0.00616

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs41292027; hg19: chr12-64895099;