14-91800333-C-A

Variant summary

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

The NM_001128596.3(TC2N):c.509G>T(p.Gly170Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000624 in 1,603,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G170W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TC2N
NM_001128596.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

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=0.10061884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TC2N	NM_001128596.3 linkuse as main transcript	c.509G>T	p.Gly170Val	missense_variant	5/12	ENST00000435962.7
TC2N	NM_001128595.3 linkuse as main transcript	c.509G>T	p.Gly170Val	missense_variant	5/12
TC2N	NM_152332.6 linkuse as main transcript	c.509G>T	p.Gly170Val	missense_variant	5/12
TC2N	NM_001289134.2 linkuse as main transcript	c.509G>T	p.Gly170Val	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TC2N	ENST00000435962.7 linkuse as main transcript	c.509G>T	p.Gly170Val	missense_variant	5/12	2	NM_001128596.3	P1	Q8N9U0-1
TC2N	ENST00000340892.9 linkuse as main transcript	c.509G>T	p.Gly170Val	missense_variant	5/12	1		P1	Q8N9U0-1
TC2N	ENST00000360594.9 linkuse as main transcript	c.509G>T	p.Gly170Val	missense_variant	5/12	1		P1	Q8N9U0-1
TC2N	ENST00000556018.5 linkuse as main transcript	c.509G>T	p.Gly170Val	missense_variant	5/11	2			Q8N9U0-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245812

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000300

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:

0.00

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1451838

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

722384

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000137

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

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

Feb 21, 2024

The c.509G>T (p.G170V) alteration is located in exon 5 (coding exon 4) of the TC2N gene. This alteration results from a G to T substitution at nucleotide position 509, causing the glycine (G) at amino acid position 170 to be replaced by a valine (V). 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

0.076

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.046

T;T;T;.

Eigen

Benign

0.042

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.69

M_CAP

Benign

0.0093

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.1

N;N;N;D

REVEL

Benign

0.048

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Benign

0.46

T;T;T;T

Polyphen

0.87

P;P;P;B

Vest4

0.18

MutPred

0.23

Loss of catalytic residue at P166 (P = 0.0829);Loss of catalytic residue at P166 (P = 0.0829);Loss of catalytic residue at P166 (P = 0.0829);Loss of catalytic residue at P166 (P = 0.0829);

MVP

0.26

MPC

0.054

ClinPred

0.42

GERP RS

4.4

Varity_R

0.20

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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