rs200821440

Variant names:

• chr15-42840406-C-G
• rs200821440
• NM_173500.4:c.245G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_173500.4(TTBK2):​c.245G>C​(p.Gly82Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,613,836 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 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: TTBK2 NM_173500.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 7.21
• Publications: 7 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.17650867).
• BP6: Variant 15-42840406-C-G is Benign according to our data. Variant chr15-42840406-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448754.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000289 (44/152138) while in subpopulation NFE AF = 0.000427 (29/67990). AF 95% confidence interval is 0.000304. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 44 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTBK2	NM_173500.4	MANE Select	c.245G>C	p.Gly82Ala	missense	Exon 4 of 15	NP_775771.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTBK2	ENST00000267890.11	TSL:5 MANE Select	c.245G>C	p.Gly82Ala	missense	Exon 4 of 15	ENSP00000267890.6
	TTBK2	ENST00000567840.5	TSL:1	c.245G>C	p.Gly82Ala	missense	Exon 4 of 12	ENSP00000455734.1
	TTBK2	ENST00000567274.5	TSL:5	c.245G>C	p.Gly82Ala	missense	Exon 4 of 11	ENSP00000457489.1

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000257 AC: 64 AN: 249482 AF XY: 0.000310

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000263 AC: 385 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.000271 AC XY: 197 AN XY: 727154

African (AFR) AF: 0.000597 AC: 20 AN: 33474

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5766

European-Non Finnish (NFE) AF: 0.000255 AC: 283 AN: 1111910

Other (OTH) AF: 0.000397 AC: 24 AN: 60386

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74384

African (AFR) AF: 0.000169 AC: 7 AN: 41482

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000427 AC: 29 AN: 67990

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.000208

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.000290 AC: 35

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Benign	0.95
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.27	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.18	T
PhyloP100		7.2
PROVEAN	Benign	-0.030	N
MVP		0.57
ClinPred		0.26	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
Mutation Taster		=27/73	disease causing

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

Other links and lift over

dbSNP: rs200821440; hg19: chr15-43132604; COSMIC: COSV99142636;