Genetic Variant TTBK1:p.Gly623Val (chr6-43263232-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_032538.3(TTBK1):c.1868G>T(p.Gly623Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,570,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G623A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

TTBK1
NM_032538.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.86

Publications

25 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060917735).

BS2

High AC in GnomAd4 at 134 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032538.3. 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
	TTBK1	NM_032538.3	MANE Select	c.1868G>T	p.Gly623Val	missense	Exon 13 of 15	NP_115927.1	Q5TCY1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTBK1	ENST00000259750.9	TSL:1 MANE Select	c.1868G>T	p.Gly623Val	missense	Exon 13 of 15	ENSP00000259750.4	Q5TCY1-1
TTBK1	ENST00000703836.1		c.1868G>T	p.Gly623Val	missense	Exon 12 of 13	ENSP00000515493.1	A0A994J709
TTBK1	ENST00000304139.6	TSL:5	n.1877G>T		non_coding_transcript_exon	Exon 12 of 13

Frequencies

GnomAD3 genomes

AF:

0.000881

AC:

134

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000146

AC:

AN:

178416

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.00231

Gnomad AMR exome

AF:

0.0000724

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000832

AC:

118

AN:

1418036

Hom.:

Cov.:

AF XY:

0.0000727

AC XY:

AN XY:

701112

show subpopulations

African (AFR)

AF:

0.00269

AC:

AN:

32696

American (AMR)

AF:

0.000129

AC:

AN:

38896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25094

East Asian (EAS)

AF:

0.00

AC:

AN:

37828

South Asian (SAS)

AF:

0.0000743

AC:

AN:

80768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

9.18e-7

AC:

AN:

1089280

Other (OTH)

AF:

0.000307

AC:

AN:

58558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000881

AC:

134

AN:

152184

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00303

AC:

126

AN:

41530

American (AMR)

AF:

0.000327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67982

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000270

Hom.:

1796

ExAC

AF:

0.000173

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0066

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.13

M_CAP

Benign

0.015

MetaRNN

Benign

0.0061

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

1.9

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.14

REVEL

Benign

0.079

Sift

Uncertain

0.0050

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.14

MVP

0.043

MPC

0.42

ClinPred

0.025

GERP RS

3.8

Varity_R

0.12

gMVP

0.24

Mutation Taster

=45/155

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over