chr12-64480322-A-C

Variant names:

• chr12-64480322-A-C
• rs7303577
• NM_013254.4:c.812+200A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_013254.4(TBK1):​c.812+200A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 152,190 control chromosomes in the GnomAD database, including 1,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.15 (1967 hom., cov: 32)
• Consequence: TBK1 NM_013254.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.222
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-64480322-A-C is Benign according to our data. Variant chr12-64480322-A-C is described in ClinVar as Benign. ClinVar VariationId is 1285973.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

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.812+200A>C		intron	N/A	NP_037386.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBK1	ENST00000331710.10	TSL:1 MANE Select	c.812+200A>C		intron	N/A	ENSP00000329967.5
	TBK1	ENST00000650790.1		c.812+200A>C		intron	N/A	ENSP00000498995.1
	TBK1	ENST00000911930.1		c.812+200A>C		intron	N/A	ENSP00000581989.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22332 AN: 152072 Hom.: 1960 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.164

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.147 AC: 22370 AN: 152190 Hom.: 1967 Cov.: 32 AF XY: 0.146 AC XY: 10873 AN XY: 74394

African (AFR) AF: 0.234 AC: 9706 AN: 41506

American (AMR) AF: 0.111 AC: 1701 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 808 AN: 3470

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5184

South Asian (SAS) AF: 0.129 AC: 622 AN: 4824

European-Finnish (FIN) AF: 0.117 AC: 1241 AN: 10594

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7632 AN: 68000

Other (OTH) AF: 0.162 AC: 342 AN: 2112

Alfa AF: 0.147 Hom.: 404

Bravo AF: 0.149

Asia WGS AF: 0.0970 AC: 336 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.5
DANN	Benign	0.65
PhyloP100		-0.22
PromoterAI		-0.017	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7303577; hg19: chr12-64874102;