Genetic Variant TC2N:p.Pro477Ala (chr14-91783144-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001128596.3(TC2N):c.1429C>G(p.Pro477Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000974 in 1,611,280 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: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

TC2N
NM_001128596.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.28

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TC2N	NM_001128596.3 link	c.1429C>G	p.Pro477Ala	missense_variant	Exon 12 of 12	ENST00000435962.7	NP_001122068.2	Q8N9U0-1
TC2N	NM_001128595.3 link	c.1429C>G	p.Pro477Ala	missense_variant	Exon 12 of 12		NP_001122067.2	Q8N9U0-1
TC2N	NM_152332.6 link	c.1429C>G	p.Pro477Ala	missense_variant	Exon 12 of 12		NP_689545.2	Q8N9U0-1
TC2N	NM_001289134.2 link	c.1237C>G	p.Pro413Ala	missense_variant	Exon 11 of 11		NP_001276063.2	Q8N9U0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TC2N	ENST00000435962.7 link	c.1429C>G	p.Pro477Ala	missense_variant	Exon 12 of 12	2	NM_001128596.3	ENSP00000387882.2		Q8N9U0-1

Frequencies

GnomAD3 genomes

AF:

0.0000922

AC:

AN:

151790

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250586

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135488

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000980

AC:

143

AN:

1459490

Hom.:

Cov.:

AF XY:

0.0000923

AC XY:

AN XY:

726080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000922

AC:

AN:

151790

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74130

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000546

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

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1429C>G (p.P477A) alteration is located in exon 12 (coding exon 11) of the TC2N gene. This alteration results from a C to G substitution at nucleotide position 1429, causing the proline (P) at amino acid position 477 to be replaced by an alanine (A). 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

Uncertain

0.53

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T;T;.;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.032

MetaRNN

Pathogenic

0.88

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;M;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-7.2

D;D;D;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.67

MutPred

0.76

Loss of catalytic residue at P477 (P = 0.0102);Loss of catalytic residue at P477 (P = 0.0102);Loss of catalytic residue at P477 (P = 0.0102);.;.;

MVP

0.53

MPC

0.32

ClinPred

0.81

GERP RS

5.6

Varity_R

0.59

gMVP

0.50

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