Variant 14-91802325-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001128596.3(TC2N):c.398A>G(p.Tyr133Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,610,232 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 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

TC2N
NM_001128596.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17

Variant links:

Genes affected

TC2N (HGNC:19859): (tandem C2 domains, nuclear) Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TC2N links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17542562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TC2N	NM_001128596.3 linkuse as main transcript	c.398A>G	p.Tyr133Cys	missense_variant	4/12	ENST00000435962.7	NP_001122068.2
TC2N	NM_001128595.3 linkuse as main transcript	c.398A>G	p.Tyr133Cys	missense_variant	4/12		NP_001122067.2
TC2N	NM_152332.6 linkuse as main transcript	c.398A>G	p.Tyr133Cys	missense_variant	4/12		NP_689545.2
TC2N	NM_001289134.2 linkuse as main transcript	c.398A>G	p.Tyr133Cys	missense_variant	4/11		NP_001276063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TC2N	ENST00000435962.7 linkuse as main transcript	c.398A>G	p.Tyr133Cys	missense_variant	4/12	2	NM_001128596.3	ENSP00000387882	P1	Q8N9U0-1
TC2N	ENST00000340892.9 linkuse as main transcript	c.398A>G	p.Tyr133Cys	missense_variant	4/12	1		ENSP00000343199	P1	Q8N9U0-1
TC2N	ENST00000360594.9 linkuse as main transcript	c.398A>G	p.Tyr133Cys	missense_variant	4/12	1		ENSP00000353802	P1	Q8N9U0-1
TC2N	ENST00000556018.5 linkuse as main transcript	c.398A>G	p.Tyr133Cys	missense_variant	4/11	2		ENSP00000451317		Q8N9U0-2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

246756

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000609

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:

0.00

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.00000892

AC:

AN:

1457930

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

725108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000159

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.000155

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

Nov 21, 2023

The c.398A>G (p.Y133C) alteration is located in exon 4 (coding exon 3) of the TC2N gene. This alteration results from a A to G substitution at nucleotide position 398, causing the tyrosine (Y) at amino acid position 133 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

0.074

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

T;T;T;.

Eigen

Benign

-0.066

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.77

M_CAP

Benign

0.0088

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.082

Sift

Benign

0.043

D;D;D;T

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.85

P;P;P;D

Vest4

0.52

MutPred

0.42

Loss of phosphorylation at Y133 (P = 0.0266);Loss of phosphorylation at Y133 (P = 0.0266);Loss of phosphorylation at Y133 (P = 0.0266);Loss of phosphorylation at Y133 (P = 0.0266);

MVP

0.34

MPC

0.13

ClinPred

0.25

GERP RS

2.9

Varity_R

0.085

gMVP

0.29

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