chr12-64497641-G-T

Variant names:

• chr12-64497641-G-T
• rs768189768
• NM_013254.4:c.1960-7G>T

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.1960-7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0075 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBK1 NM_013254.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001129
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0650

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-64497641-G-T is Benign according to our data. Variant chr12-64497641-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 542556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-64497641-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBK1	NM_013254.4	c.1960-7G>T		splice_region_variant, intron_variant	Intron 18 of 20	ENST00000331710.10	NP_037386.1
TBK1	XM_005268809.2	c.1960-7G>T		splice_region_variant, intron_variant	Intron 18 of 20		XP_005268866.1
TBK1	XM_005268810.2	c.1960-7G>T		splice_region_variant, intron_variant	Intron 18 of 20		XP_005268867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBK1	ENST00000331710.10	c.1960-7G>T		splice_region_variant, intron_variant	Intron 18 of 20	1	NM_013254.4	ENSP00000329967.5

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 376 AN: 79448 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00416

Gnomad AMI AF: 0.00649

Gnomad AMR AF: 0.00431

Gnomad ASJ AF: 0.00422

Gnomad EAS AF: 0.00241

Gnomad SAS AF: 0.00184

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00505

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.00503 AC: 798 AN: 158798 AF XY: 0.00474

Gnomad AFR exome AF: 0.00354

Gnomad AMR exome AF: 0.00788

Gnomad ASJ exome AF: 0.00719

Gnomad EAS exome AF: 0.0121

Gnomad FIN exome AF: 0.00643

Gnomad NFE exome AF: 0.00356

Gnomad OTH exome AF: 0.00328

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00751 AC: 5310 AN: 706960 Hom.: 0 Cov.: 20 AF XY: 0.00713 AC XY: 2588 AN XY: 362892

Gnomad4 AFR exome AF: 0.00499 AC: 82 AN: 16418

Gnomad4 AMR exome AF: 0.00807 AC: 166 AN: 20572

Gnomad4 ASJ exome AF: 0.00674 AC: 98 AN: 14540

Gnomad4 EAS exome AF: 0.00690 AC: 188 AN: 27240

Gnomad4 SAS exome AF: 0.0103 AC: 438 AN: 42648

Gnomad4 FIN exome AF: 0.0105 AC: 387 AN: 36758

Gnomad4 NFE exome AF: 0.00729 AC: 3753 AN: 514498

Gnomad4 Remaining exome AF: 0.00600 AC: 188 AN: 31348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (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: 0.00473 AC: 376 AN: 79490 Hom.: 0 Cov.: 23 AF XY: 0.00506 AC XY: 191 AN XY: 37732

Gnomad4 AFR AF: 0.00415 AC: 0.00414886 AN: 0.00414886

Gnomad4 AMR AF: 0.00431 AC: 0.00431034 AN: 0.00431034

Gnomad4 ASJ AF: 0.00422 AC: 0.00421941 AN: 0.00421941

Gnomad4 EAS AF: 0.00242 AC: 0.0024188 AN: 0.0024188

Gnomad4 SAS AF: 0.00185 AC: 0.00184911 AN: 0.00184911

Gnomad4 FIN AF: 0.0119 AC: 0.0118613 AN: 0.0118613

Gnomad4 NFE AF: 0.00505 AC: 0.00504574 AN: 0.00504574

Gnomad4 OTH AF: 0.00200 AC: 0.002 AN: 0.002

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

Alfa AF: 0.00569 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 01, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.9
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs768189768; hg19: chr12-64891421;