rs370495535

chr15-42777166-C-Achr15-42777166-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173500.4(TTBK2):c.1274G>T(p.Arg425Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. R425H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTBK2 NM_173500.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37797874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTBK2	NM_173500.4	c.1274G>T	p.Arg425Leu	missense_variant	12/15	ENST00000267890.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTBK2	ENST00000267890.11	c.1274G>T	p.Arg425Leu	missense_variant	12/15	5	NM_173500.4	P1
TTBK2	ENST00000567840.5	c.1274G>T	p.Arg425Leu	missense_variant	12/12	1
TTBK2	ENST00000567274.5	c.1169G>T	p.Arg390Leu	missense_variant	11/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;T;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	2.0	M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	N;.;N;D
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.68	P;B;P;.
Vest4		0.67
MutPred		0.48		Loss of methylation at R425 (P = 0.0245);.;Loss of methylation at R425 (P = 0.0245);.;
MVP		0.21
MPC		0.96
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.31
gMVP		0.43

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

Other links and lift over

dbSNP: rs370495535; hg19: chr15-43069364;