14-91792375-T-C

Variant summary

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

The NM_001128596.3(TC2N):c.1039A>G(p.Lys347Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000119 in 1,433,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TC2N NM_001128596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.39

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TC2N	NM_001128596.3	c.1039A>G	p.Lys347Glu	missense_variant	9/12	ENST00000435962.7
TC2N	NM_001128595.3	c.1039A>G	p.Lys347Glu	missense_variant	9/12
TC2N	NM_152332.6	c.1039A>G	p.Lys347Glu	missense_variant	9/12
TC2N	NM_001289134.2	c.856-4748A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TC2N	ENST00000435962.7	c.1039A>G	p.Lys347Glu	missense_variant	9/12	2	NM_001128596.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000207 AC: 5 AN: 241220 Hom.: 0 AF XY: 0.0000383 AC XY: 5 AN XY: 130662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000104

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 17 AN: 1433588 Hom.: 0 Cov.: 30 AF XY: 0.0000154 AC XY: 11 AN XY: 712532

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000480

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000149

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 9.11e-7

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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

Apr 27, 2023

The c.1039A>G (p.K347E) alteration is located in exon 9 (coding exon 8) of the TC2N gene. This alteration results from a A to G substitution at nucleotide position 1039, causing the lysine (K) at amino acid position 347 to be replaced by a glutamic acid (E). 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	0.55
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.041	T;T;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Uncertain	2.2	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.88	N;N;N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.026	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.70
MutPred		0.52		Loss of ubiquitination at K347 (P = 0.0103);Loss of ubiquitination at K347 (P = 0.0103);Loss of ubiquitination at K347 (P = 0.0103);.;
MVP		0.84
MPC		0.36
ClinPred		0.71	D
GERP RS		5.5
Varity_R		0.33
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs769904377; hg19: chr14-92258719; COSMIC: COSV61746139;