rs371275822

Variant names:

• chr12-64497638-G-T
• rs371275822
• NM_013254.4:c.1960-10G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-64497638-G-T
• chr12-64497638-G-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_013254.4(TBK1):​c.1960-10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (0 hom., cov: 0)
  • Exomes 𝑓: 0.014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBK1 NM_013254.4 intron
• Scores: Splicing: ADA: 0.0007784
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.199
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-64497638-G-T is Benign according to our data. Variant chr12-64497638-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013254.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	NM_013254.4	MANE Select	c.1960-10G>T		intron	N/A	NP_037386.1	Q9UHD2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	ENST00000331710.10	TSL:1 MANE Select	c.1960-10G>T		intron	N/A	ENSP00000329967.5	Q9UHD2
	TBK1	ENST00000650790.1		c.1960-10G>T		intron	N/A	ENSP00000498995.1	Q9UHD2
	TBK1	ENST00000911930.1		c.1960-10G>T		intron	N/A	ENSP00000581989.1

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 1514 AN: 37732 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.0526

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.0419

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.0517

Gnomad NFE AF: 0.0507

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0148 AC: 647 AN: 43572 AF XY: 0.0154

Gnomad AFR exome AF: 0.00737

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0252

Gnomad EAS exome AF: 0.0233

Gnomad FIN exome AF: 0.0591

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.0187

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0138 AC: 6794 AN: 491534 Hom.: 0 Cov.: 17 AF XY: 0.0145 AC XY: 3583 AN XY: 246610

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0103 AC: 126 AN: 12220

American (AMR) AF: 0.0256 AC: 227 AN: 8850

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 136 AN: 9716

East Asian (EAS) AF: 0.00957 AC: 202 AN: 21106

South Asian (SAS) AF: 0.0457 AC: 768 AN: 16794

European-Finnish (FIN) AF: 0.0285 AC: 611 AN: 21414

Middle Eastern (MID) AF: 0.00906 AC: 16 AN: 1766

European-Non Finnish (NFE) AF: 0.0118 AC: 4452 AN: 376256

Other (OTH) AF: 0.0109 AC: 256 AN: 23412

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0401 AC: 1514 AN: 37756 Hom.: 0 Cov.: 0 AF XY: 0.0403 AC XY: 746 AN XY: 18494

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0311 AC: 378 AN: 12172

American (AMR) AF: 0.0372 AC: 145 AN: 3896

Ashkenazi Jewish (ASJ) AF: 0.0526 AC: 41 AN: 780

East Asian (EAS) AF: 0.0170 AC: 24 AN: 1412

South Asian (SAS) AF: 0.0422 AC: 57 AN: 1350

European-Finnish (FIN) AF: 0.0253 AC: 53 AN: 2094

Middle Eastern (MID) AF: 0.0536 AC: 3 AN: 56

European-Non Finnish (NFE) AF: 0.0507 AC: 777 AN: 15324

Other (OTH) AF: 0.0583 AC: 28 AN: 480

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Glaucoma 1, open angle, P (2)
-	-	1	Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.0
DANN	Benign	0.76
PhyloP100		-0.20
PromoterAI		-0.014	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00078
dbscSNV1_RF	Benign	0.012
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs371275822;

hg19: chr12-64891418;