Genetic Variant TLDC2:p.Arg62Trp (chr20-36878049-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080628.3(TLDC2):c.184C>T(p.Arg62Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

TLDC2
NM_080628.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.20

Variant links:

Genes affected

TLDC2 (HGNC:16112): (TBC/LysM-associated domain containing 2) Predicted to be involved in response to oxidative stress. Predicted to act upstream of or within negative regulation of oxidative stress-induced neuron death. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TLDC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLDC2	NM_080628.3 link	c.184C>T	p.Arg62Trp	missense_variant	Exon 2 of 7	ENST00000217320.8	NP_542195.1	A0PJX2
TLDC2	XM_017027674.2 link	c.-100C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5		XP_016883163.1
TLDC2	NM_001304783.1 link	c.184C>T	p.Arg62Trp	missense_variant	Exon 2 of 6		NP_001291712.1	A0PJX2
TLDC2	XM_017027674.2 link	c.-100C>T		5_prime_UTR_variant	Exon 1 of 5		XP_016883163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLDC2	ENST00000217320.8 link	c.184C>T	p.Arg62Trp	missense_variant	Exon 2 of 7	1	NM_080628.3	ENSP00000217320.3		A0PJX2
TLDC2	ENST00000602922.5 link	c.184C>T	p.Arg62Trp	missense_variant	Exon 2 of 6	1		ENSP00000473323.1		A0PJX2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000522

AC:

AN:

248852

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134520

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1460272

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726396

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.184C>T (p.R62W) alteration is located in exon 2 (coding exon 2) of the TLDC2 gene. This alteration results from a C to T substitution at nucleotide position 184, causing the arginine (R) at amino acid position 62 to be replaced by a tryptophan (W). 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

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.85

.;D

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.0

.;D

REVEL

Benign

0.15

Sift

Uncertain

0.014

.;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.99

D;D

Vest4

0.58

MVP

0.52

MPC

0.28

ClinPred

0.50

GERP RS

2.5

Varity_R

0.082

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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