rs752400040

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_173500.4(TTBK2):c.2299G>A(p.Val767Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

TTBK2
NM_173500.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.111

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03226629).

BP6

Variant 15-42752947-C-T is Benign according to our data. Variant chr15-42752947-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTBK2	NM_173500.4 link	c.2299G>A	p.Val767Met	missense_variant	Exon 14 of 15	ENST00000267890.11	NP_775771.3	Q6IQ55-1Q8IWY7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTBK2	ENST00000267890.11 link	c.2299G>A	p.Val767Met	missense_variant	Exon 14 of 15	5	NM_173500.4	ENSP00000267890.6		Q6IQ55-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152236

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:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

249544

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135386

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:

0.0000327

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000674

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000125

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 22, 2017

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Oct 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTBK2 c.2299G>A (p.Val767Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249544 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTBK2 causing Spinocerebellar Ataxia Type 11, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2299G>A in individuals affected with Spinocerebellar Ataxia Type 11 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 586780). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.1

DANN

Benign

0.73

DEOGEN2

Benign

0.045

T;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.0084

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.16

N;.

REVEL

Benign

0.065

Sift

Benign

0.17

T;.

Sift4G

Benign

0.10

T;T

Polyphen

0.0

B;.

Vest4

0.093

MutPred

0.18

Loss of sheet (P = 0.0104);.;

MVP

0.28

MPC

0.24

ClinPred

0.039

GERP RS

-0.16

Varity_R

0.032

gMVP

0.042

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over