Genetic Variant NM_003318.5:c.656T>C (chr6-80011476-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003318.5(TTK):c.656T>C(p.Leu219Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,564 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L219H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TTK
NM_003318.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.289

Variant links:

Genes affected

TTK (HGNC:12401): (TTK protein kinase) This gene encodes a dual specificity protein kinase with the ability to phosphorylate tyrosine, serine and threonine. Associated with cell proliferation, this protein is essential for chromosome alignment at the centromere during mitosis and is required for centrosome duplication. It has been found to be a critical mitotic checkpoint protein for accurate segregation of chromosomes during mitosis. Tumorigenesis may occur when this protein fails to degrade and produces excess centrosomes resulting in aberrant mitotic spindles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

TTK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4007714).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTK	NM_003318.5 link	c.656T>C	p.Leu219Pro	missense_variant	Exon 6 of 22	ENST00000369798.7	NP_003309.2	P33981-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTK	ENST00000369798.7 link	c.656T>C	p.Leu219Pro	missense_variant	Exon 6 of 22	1	NM_003318.5	ENSP00000358813.2	P33981-1
TTK	ENST00000230510.7 link	c.656T>C	p.Leu219Pro	missense_variant	Exon 6 of 22	2		ENSP00000230510.3	P33981-2
TTK	ENST00000509894.5 link	c.656T>C	p.Leu219Pro	missense_variant	Exon 6 of 22	5		ENSP00000422936.1	P33981-2
TTK	ENST00000430061.2 link	n.517-14T>C		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1455564

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723946

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33206

American (AMR)

AF:

0.00

AC:

AN:

43202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25910

East Asian (EAS)

AF:

0.00

AC:

AN:

39518

South Asian (SAS)

AF:

0.00

AC:

AN:

84658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109896

Other (OTH)

AF:

0.00

AC:

AN:

60106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.079

.;.;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.56

.;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.40

T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.2

M;M;M

PhyloP100

-0.29

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.5

N;N;N

REVEL

Uncertain

0.44

Sift

Uncertain

0.0020

D;D;D

Sift4G

Benign

0.12

T;T;T

Polyphen

0.84

.;.;P

Vest4

0.56

MutPred

0.14

Gain of glycosylation at S216 (P = 0.0598);Gain of glycosylation at S216 (P = 0.0598);Gain of glycosylation at S216 (P = 0.0598);

MVP

0.69

MPC

0.23

ClinPred

0.51

GERP RS

0.97

Varity_R

0.12

gMVP

0.51

Mutation Taster

=93/7

polymorphism

(source)

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

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NM_003318.5:c.656T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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