dbSNP rs36104367: TTBK2:p.Lys1241Thr (chr15-42745808-T-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_173500.4(TTBK2):c.3722A>C(p.Lys1241Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000273 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

TTBK2
NM_173500.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.65

Publications

3 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: Orphanet, Labcorp Genetics (formerly Invitae)

TTBK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18443385).

BP6

Variant 15-42745808-T-G is Benign according to our data. Variant chr15-42745808-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 425066.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00029 (424/1461818) while in subpopulation NFE AF = 0.000365 (406/1112012). AF 95% confidence interval is 0.000336. There are 0 homozygotes in GnomAdExome4. There are 199 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173500.4. 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
	TTBK2	NM_173500.4	MANE Select	c.3722A>C	p.Lys1241Thr	missense	Exon 15 of 15	NP_775771.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTBK2	ENST00000267890.11	TSL:5 MANE Select	c.3722A>C	p.Lys1241Thr	missense	Exon 15 of 15	ENSP00000267890.6	Q6IQ55-1
TTBK2	ENST00000903061.1		c.3722A>C	p.Lys1241Thr	missense	Exon 15 of 15	ENSP00000573120.1
TTBK2	ENST00000903062.1		c.3656A>C	p.Lys1219Thr	missense	Exon 14 of 14	ENSP00000573121.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000108

AC:

AN:

249570

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000221

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000290

AC:

424

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

199

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000365

AC:

406

AN:

1112012

Other (OTH)

AF:

0.000199

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000112

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41454

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000214

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Spinocerebellar ataxia type 11 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

M_CAP

Benign

0.055

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.7

PhyloP100

5.6

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.2

REVEL

Benign

0.20

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.042

Polyphen

1.0

Vest4

0.56

MVP

0.20

MPC

0.95

ClinPred

0.19

GERP RS

5.2

Varity_R

0.47

gMVP

0.39

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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