14-91802329-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001128596.3(TC2N):c.394A>G(p.Met132Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,458,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TC2N NM_001128596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

Genes affected

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

ACMG classification

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=0.09746361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TC2N	NM_001128596.3	c.394A>G	p.Met132Val	missense_variant	4/12	ENST00000435962.7
TC2N	NM_001128595.3	c.394A>G	p.Met132Val	missense_variant	4/12
TC2N	NM_152332.6	c.394A>G	p.Met132Val	missense_variant	4/12
TC2N	NM_001289134.2	c.394A>G	p.Met132Val	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TC2N	ENST00000435962.7	c.394A>G	p.Met132Val	missense_variant	4/12	2	NM_001128596.3	P1
TC2N	ENST00000340892.9	c.394A>G	p.Met132Val	missense_variant	4/12	1		P1
TC2N	ENST00000360594.9	c.394A>G	p.Met132Val	missense_variant	4/12	1		P1
TC2N	ENST00000556018.5	c.394A>G	p.Met132Val	missense_variant	4/11	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000809 AC: 2 AN: 247338 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

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: 0.00000549 AC: 8 AN: 1458512 Hom.: 0 Cov.: 33 AF XY: 0.00000689 AC XY: 5 AN XY: 725396

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The c.394A>G (p.M132V) 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 394, causing the methionine (M) at amino acid position 132 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	0.070
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	16
Dann	Benign	0.78
DEOGEN2	Benign	0.023	T;T;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.60	D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.097	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.88	N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.17	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.13
MutPred		0.24		Gain of catalytic residue at M132 (P = 0.0248);Gain of catalytic residue at M132 (P = 0.0248);Gain of catalytic residue at M132 (P = 0.0248);Gain of catalytic residue at M132 (P = 0.0248);
MVP		0.17
MPC		0.047
ClinPred		0.054	T
GERP RS		2.9
Varity_R		0.062
gMVP		0.49

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

Other links and lift over

dbSNP: rs1251270204; hg19: chr14-92268673; COSMIC: COSV105238242; COSMIC: COSV105238242;