chr6-43252789-C-G

Position:

• chr6-43252789-C-G

Variant summary

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

The NM_032538.3(TTBK1):​c.159C>G​(p.Asp53Glu) variant causes a missense change involving the alteration of a non-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: 31)
• Consequence: TTBK1 NM_032538.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.482

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.159C>G	p.Asp53Glu	missense_variant	3/15	ENST00000259750.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTBK1	ENST00000259750.9	c.159C>G	p.Asp53Glu	missense_variant	3/15	1	NM_032538.3	P3
TTBK1	ENST00000703836.1	c.159C>G	p.Asp53Glu	missense_variant	2/13			A2
TTBK1	ENST00000304139.6	n.168C>G		non_coding_transcript_exon_variant	2/13	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Jan 17, 2023

The c.159C>G (p.D53E) alteration is located in exon 3 (coding exon 2) of the TTBK1 gene. This alteration results from a C to G substitution at nucleotide position 159, causing the aspartic acid (D) at amino acid position 53 to be replaced by a glutamic acid (E). 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	0.99
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.016	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.55		Loss of phosphorylation at Y49 (P = 0.1401);.;
MVP		0.36
MPC		2.6
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.66
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: chr6-43220527;