rs373500080

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The ENST00000567840.5(TTBK2):c.1408T>C(p.Trp470Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TTBK2
ENST00000567840.5 missense

Scores

Splicing: ADA: 0.8965

Clinical Significance

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

Conservation

PhyloP100: 6.63

Publications

0 publications found

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]

TTBK2 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 11
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

TTBK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 15-42777032-A-G is Benign according to our data. Variant chr15-42777032-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 448749. Variant chr15-42777032-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 448749. Variant chr15-42777032-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 448749. Variant chr15-42777032-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 448749. Variant chr15-42777032-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 448749. Variant chr15-42777032-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 448749.

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTBK2	NM_173500.4 link	c.1408T>C	p.Cys470Arg	missense_variant, splice_region_variant	Exon 12 of 15	ENST00000267890.11	NP_775771.3	Q6IQ55-1Q8IWY7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTBK2	ENST00000567840.5 link	c.1408T>C	p.Trp470Arg	missense_variant	Exon 12 of 12	1		ENSP00000455734.1	Q6IQ55-3
TTBK2	ENST00000267890.11 link	c.1408T>C	p.Cys470Arg	missense_variant, splice_region_variant	Exon 12 of 15	5	NM_173500.4	ENSP00000267890.6	Q6IQ55-1
TTBK2	ENST00000567274.5 link	c.1303T>C	p.Trp435Arg	missense_variant	Exon 11 of 11	5		ENSP00000457489.1	A0A0B4J292

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000128

AC:

AN:

249160

AF XY:

0.000126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000114

AC:

166

AN:

1461598

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000135

AC:

150

AN:

1111788

Other (OTH)

AF:

0.000116

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.000105

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

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:

0.000307

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000993

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1408T>C (p.C470R) alteration is located in exon 12 (coding exon 11) of the TTBK2 gene. This alteration results from a T to C substitution at nucleotide position 1408, causing the cysteine (C) at amino acid position 470 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Jan 31, 2024

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

6.6

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.23

N;.

REVEL

Benign

0.16

Sift

Benign

0.20

T;.

Sift4G

Benign

0.39

T;T

Polyphen

0.14

B;.

Vest4

0.81

MVP

0.082

MPC

1.1

ClinPred

0.070

GERP RS

5.6

Varity_R

0.48

gMVP

0.49

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.90

dbscSNV1_RF

Benign

0.71

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over