Genetic Variant TC2N:p.Lys173Arg (chr14-91800324-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001128596.3(TC2N):c.518A>G(p.Lys173Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,605,552 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TC2N
NM_001128596.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.221

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05840093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TC2N	NM_001128596.3 link	c.518A>G	p.Lys173Arg	missense_variant	Exon 5 of 12	ENST00000435962.7	NP_001122068.2	Q8N9U0-1
TC2N	NM_001128595.3 link	c.518A>G	p.Lys173Arg	missense_variant	Exon 5 of 12		NP_001122067.2	Q8N9U0-1
TC2N	NM_152332.6 link	c.518A>G	p.Lys173Arg	missense_variant	Exon 5 of 12		NP_689545.2	Q8N9U0-1
TC2N	NM_001289134.2 link	c.518A>G	p.Lys173Arg	missense_variant	Exon 5 of 11		NP_001276063.2	Q8N9U0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TC2N	ENST00000435962.7 link	c.518A>G	p.Lys173Arg	missense_variant	Exon 5 of 12	2	NM_001128596.3	ENSP00000387882.2	Q8N9U0-1
TC2N	ENST00000340892.9 link	c.518A>G	p.Lys173Arg	missense_variant	Exon 5 of 12	1		ENSP00000343199.5	Q8N9U0-1
TC2N	ENST00000360594.9 link	c.518A>G	p.Lys173Arg	missense_variant	Exon 5 of 12	1		ENSP00000353802.5	Q8N9U0-1
TC2N	ENST00000556018.5 link	c.518A>G	p.Lys173Arg	missense_variant	Exon 5 of 11	2		ENSP00000451317.1	Q8N9U0-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453442

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723140

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

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:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.518A>G (p.K173R) alteration is located in exon 5 (coding exon 4) of the TC2N gene. This alteration results from a A to G substitution at nucleotide position 518, causing the lysine (K) at amino acid position 173 to be replaced by an arginine (R). 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

0.070

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0094

T;T;T;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.56

M_CAP

Benign

0.0024

MetaRNN

Benign

0.058

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.97

L;L;L;L

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.47

N;N;N;N

REVEL

Benign

0.041

Sift

Benign

0.27

T;T;T;T

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.037

MutPred

0.28

Loss of ubiquitination at K173 (P = 0.0014);Loss of ubiquitination at K173 (P = 0.0014);Loss of ubiquitination at K173 (P = 0.0014);Loss of ubiquitination at K173 (P = 0.0014);

MVP

0.27

MPC

0.040

ClinPred

0.10

GERP RS

2.7

Varity_R

0.061

gMVP

0.27

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