6-43255101-C-T

Position:

• chr6-43255101-C-T

Variant summary

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

The NM_032538.3(TTBK1):​c.629C>T​(p.Ala210Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: TTBK1 NM_032538.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33

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]

ACMG classification

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	UniProt
TTBK1	NM_032538.3	c.629C>T	p.Ala210Val	missense_variant	7/15	ENST00000259750.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTBK1	ENST00000259750.9	c.629C>T	p.Ala210Val	missense_variant	7/15	1	NM_032538.3	P3
TTBK1	ENST00000703836.1	c.629C>T	p.Ala210Val	missense_variant	6/13			A2
TTBK1	ENST00000304139.6	n.638C>T		non_coding_transcript_exon_variant	6/13	5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2021

The c.629C>T (p.A210V) alteration is located in exon 7 (coding exon 6) of the TTBK1 gene. This alteration results from a C to T substitution at nucleotide position 629, causing the alanine (A) at amino acid position 210 to be replaced by a valine (V). 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	Pathogenic	1.0
BayesDel_addAF	Benign	0.0099	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.29
Sift	Benign	0.042	D;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.69
MutPred		0.43		Loss of disorder (P = 0.0773);.;
MVP		0.34
MPC		2.5
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.68
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-43222839;