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GeneBe

15-42777166-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_173500.4(TTBK2):c.1274G>A(p.Arg425His) variant causes a missense change. The variant allele was found at a frequency of 0.0000799 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000083 ( 1 hom. )

Consequence

TTBK2
NM_173500.4 missense

Scores

8
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 4.46
Variant links:
Genes affected
TTBK2 (HGNC:19141): (tau tubulin kinase 2) This gene encodes a serine-threonine kinase that putatively phosphorylates tau and tubulin proteins. Mutations in this gene cause spinocerebellar ataxia type 11 (SCA11); a neurodegenerative disease characterized by progressive ataxia and atrophy of the cerebellum and brainstem. [provided by RefSeq, Aug 2009]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12802848).
BP6
Variant 15-42777166-C-T is Benign according to our data. Variant chr15-42777166-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448746.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000828 (121/1461890) while in subpopulation MID AF= 0.00468 (27/5768). AF 95% confidence interval is 0.0033. There are 1 homozygotes in gnomad4_exome. There are 66 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TTBK2NM_173500.4 linkuse as main transcriptc.1274G>A p.Arg425His missense_variant 12/15 ENST00000267890.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TTBK2ENST00000267890.11 linkuse as main transcriptc.1274G>A p.Arg425His missense_variant 12/155 NM_173500.4 P1Q6IQ55-1
TTBK2ENST00000567840.5 linkuse as main transcriptc.1274G>A p.Arg425His missense_variant 12/121 Q6IQ55-3
TTBK2ENST00000567274.5 linkuse as main transcriptc.1169G>A p.Arg390His missense_variant 11/115

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000561
AC:
14
AN:
249336
Hom.:
0
AF XY:
0.0000591
AC XY:
8
AN XY:
135266
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:
0.000115
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000828
AC:
121
AN:
1461890
Hom.:
1
Cov.:
31
AF XY:
0.0000908
AC XY:
66
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000746
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152274
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000115
Hom.:
0
Bravo
AF:
0.0000831
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000362
AC:
3
ExAC
AF:
0.0000827
AC:
10
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2022TTBK2: BP4 -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 22, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 425 of the TTBK2 protein (p.Arg425His). This variant is present in population databases (rs370495535, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TTBK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 448746). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TTBK2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsJun 02, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.41
Cadd
Pathogenic
28
Dann
Uncertain
1.0
DEOGEN2
Benign
0.28
T;T;.;T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
2.0
M;.;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-2.2
N;.;N;N
REVEL
Benign
0.086
Sift
Uncertain
0.013
D;.;D;D
Sift4G
Uncertain
0.0090
D;D;T;T
Polyphen
1.0
D;B;P;.
Vest4
0.34
MVP
0.39
MPC
0.96
ClinPred
0.20
T
GERP RS
4.7
Varity_R
0.14
gMVP
0.31

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.

Other links and lift over

dbSNP: rs370495535; hg19: chr15-43069364; API