Variant chr6-43259580-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032538.3(TTBK1):c.1298C>G(p.Ser433Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,456,428 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TTBK1
NM_032538.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.29

Variant links:

Genes affected

TTBK1 (HGNC:19140): (tau tubulin kinase 1) Summary:This gene belongs to the casein kinase 1 superfamily. The encoded protein is a neuron-specific, serine/threonine and tyrosine kinase, which regulates phosphorylation of tau, a protein that associates with microtubule assemblies and stabilizes them. Genetic variants in this gene are associated with Alzheimer's disease. [provided by RefSeq, Jul 2016]

TTBK1 links:

TTBK1 (HGNC:):

TTBK1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTBK1	NM_032538.3 linkuse as main transcript	c.1298C>G	p.Ser433Cys	missense_variant	12/15	ENST00000259750.9	NP_115927.1	Q5TCY1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TTBK1	ENST00000259750.9 linkuse as main transcript	c.1298C>G	p.Ser433Cys	missense_variant	12/15	1	NM_032538.3	ENSP00000259750.4	Q5TCY1-1
TTBK1	ENST00000703836.1 linkuse as main transcript	c.1298C>G	p.Ser433Cys	missense_variant	11/13			ENSP00000515493.1	A0A994J709
TTBK1	ENST00000304139.6 linkuse as main transcript	n.1307C>G		non_coding_transcript_exon_variant	11/13	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000831

AC:

AN:

240784

Hom.:

AF XY:

0.00000764

AC XY:

AN XY:

130902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1456428

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724300

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

The c.1298C>G (p.S433C) alteration is located in exon 12 (coding exon 11) of the TTBK1 gene. This alteration results from a C to G substitution at nucleotide position 1298, causing the serine (S) at amino acid position 433 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.70

MutPred

0.28

Loss of phosphorylation at S433 (P = 0.0061);.;

MVP

0.28

MPC

1.0

ClinPred

0.98

GERP RS

5.1

Varity_R

0.56

gMVP

0.43

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over