Variant 6-167340670-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_031949.5(TTLL2):c.770G>C(p.Arg257Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TTLL2
NM_031949.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.24

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTLL2	NM_031949.5 linkuse as main transcript	c.770G>C	p.Arg257Pro	missense_variant	3/3	ENST00000239587.10	NP_114155.4
TTLL2	NM_001410948.1 linkuse as main transcript	c.551G>C	p.Arg184Pro	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.770G>C	p.Arg257Pro	missense_variant	3/3	1	NM_031949.5	ENSP00000239587	P2
TTLL2	ENST00000515138.1 linkuse as main transcript	c.770G>C	p.Arg257Pro	missense_variant, NMD_transcript_variant	3/6	1		ENSP00000424130
TTLL2	ENST00000649884.1 linkuse as main transcript	c.551G>C	p.Arg184Pro	missense_variant	2/2			ENSP00000497040	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251436

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

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

Dec 19, 2022

The c.770G>C (p.R257P) alteration is located in exon 3 (coding exon 3) of the TTLL2 gene. This alteration results from a G to C substitution at nucleotide position 770, causing the arginine (R) at amino acid position 257 to be replaced by a proline (P). 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

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.82

T;.

M_CAP

Benign

0.0025

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-0.38

MutationAssessor

Pathogenic

4.9

.;H

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-7.0

.;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

.;D

Vest4

0.76

MutPred

0.88

.;Loss of catalytic residue at R257 (P = 0.0367);

MVP

0.22

MPC

0.67

ClinPred

1.0

GERP RS

2.3

Varity_R

0.99

gMVP

0.97

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