15-42745803-T-C

Variant names:

• chr15-42745803-T-C
• rs1482886137
• NM_173500.4:c.3727A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173500.4(TTBK2):​c.3727A>G​(p.Ser1243Gly) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTBK2 NM_173500.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.65
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16398665).

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.3727A>G	p.Ser1243Gly	missense	Exon 15 of 15	NP_775771.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTBK2	ENST00000267890.11	TSL:5 MANE Select	c.3727A>G	p.Ser1243Gly	missense	Exon 15 of 15	ENSP00000267890.6	Q6IQ55-1
	TTBK2	ENST00000903061.1		c.3727A>G	p.Ser1243Gly	missense	Exon 15 of 15	ENSP00000573120.1
	TTBK2	ENST00000903062.1		c.3661A>G	p.Ser1221Gly	missense	Exon 14 of 14	ENSP00000573121.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0097	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.043
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.12	B
Vest4		0.54
MutPred		0.097		Loss of phosphorylation at S1243 (P = 0.0028)
MVP		0.16
MPC		0.82
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.50
gMVP		0.24
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1482886137; hg19: chr15-43038001;