15-42745104-T-TA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_173500.4(TTBK2):c.*690_*691insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 144,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (0 hom.)
• Consequence: TTBK2 NM_173500.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.625

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00164 (234/142814) while in subpopulation AFR AF= 0.00447 (175/39112). AF 95% confidence interval is 0.00393. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 229 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTBK2	NM_173500.4	c.*690_*691insT		3_prime_UTR_variant	15/15	ENST00000267890.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTBK2	ENST00000267890.11	c.*690_*691insT		3_prime_UTR_variant	15/15	5	NM_173500.4	P1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 229 AN: 142766 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000773

Gnomad ASJ AF: 0.000299

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000957

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000492

Gnomad OTH AF: 0.00258

GnomAD4 exome AF: 0.00190 AC: 4 AN: 2110 Hom.: 0 Cov.: 0 AF XY: 0.00284 AC XY: 3 AN XY: 1058

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00164 AC: 234 AN: 142814 Hom.: 0 Cov.: 32 AF XY: 0.00177 AC XY: 122 AN XY: 69084

Gnomad4 AFR AF: 0.00447

Gnomad4 AMR AF: 0.000772

Gnomad4 ASJ AF: 0.000299

Gnomad4 EAS AF: 0.000200

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000957

Gnomad4 NFE AF: 0.000492

Gnomad4 OTH AF: 0.00256

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant cerebellar ataxia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs886051160; hg19: chr15-43037302;