Variant 6-167340552-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_031949.5(TTLL2):c.652C>T(p.Arg218Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

TTLL2
NM_031949.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.339

Variant links:

Genes affected

TTLL2 (HGNC:21211): (tubulin tyrosine ligase like 2) Predicted to enable tubulin binding activity and tubulin-glutamic acid ligase activity. Predicted to be involved in microtubule cytoskeleton organization and protein polyglutamylation. Predicted to be active in cilium. [provided by Alliance of Genome Resources, Apr 2022]

TTLL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a site Essential for specifying initiation versus elongation step of the polyglutamylase activity (size 0) in uniprot entity TTLL2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21574238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTLL2	NM_031949.5 linkuse as main transcript	c.652C>T	p.Arg218Cys	missense_variant	3/3	ENST00000239587.10	NP_114155.4
TTLL2	NM_001410948.1 linkuse as main transcript	c.433C>T	p.Arg145Cys	missense_variant	2/2		NP_001397877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TTLL2	ENST00000239587.10 linkuse as main transcript	c.652C>T	p.Arg218Cys	missense_variant	3/3	1	NM_031949.5	ENSP00000239587	P2
TTLL2	ENST00000515138.1 linkuse as main transcript	c.652C>T	p.Arg218Cys	missense_variant, NMD_transcript_variant	3/6	1		ENSP00000424130
TTLL2	ENST00000649884.1 linkuse as main transcript	c.433C>T	p.Arg145Cys	missense_variant	2/2			ENSP00000497040	A2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251374

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000151

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.000261

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.652C>T (p.R218C) alteration is located in exon 3 (coding exon 3) of the TTLL2 gene. This alteration results from a C to T substitution at nucleotide position 652, causing the arginine (R) at amino acid position 218 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.026

.;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.032

LIST_S2

Uncertain

0.86

D;.

M_CAP

Benign

0.0018

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

.;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-6.1

.;D

REVEL

Benign

0.053

Sift

Uncertain

0.029

.;D

Sift4G

Pathogenic

0.0010

.;D

Polyphen

0.81

.;P

Vest4

0.24

MVP

0.030

MPC

0.17

ClinPred

0.48

GERP RS

2.6

Varity_R

0.24

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over