14-91783155-G-A

Position:

• chr14-91783155-G-A

Variant summary

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

The NM_001128596.3(TC2N):​c.1418C>T​(p.Thr473Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TC2N NM_001128596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.28

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	Protein	UniProt
TC2N	NM_001128596.3	c.1418C>T	p.Thr473Ile	missense_variant	12/12	ENST00000435962.7	NP_001122068.2
TC2N	NM_001128595.3	c.1418C>T	p.Thr473Ile	missense_variant	12/12		NP_001122067.2
TC2N	NM_152332.6	c.1418C>T	p.Thr473Ile	missense_variant	12/12		NP_689545.2
TC2N	NM_001289134.2	c.1226C>T	p.Thr409Ile	missense_variant	11/11		NP_001276063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TC2N	ENST00000435962.7	c.1418C>T	p.Thr473Ile	missense_variant	12/12	2	NM_001128596.3	ENSP00000387882	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Jun 22, 2024

The c.1418C>T (p.T473I) alteration is located in exon 12 (coding exon 11) of the TC2N gene. This alteration results from a C to T substitution at nucleotide position 1418, causing the threonine (T) at amino acid position 473 to be replaced by an isoleucine (I). 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	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;T;T;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.46	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.23	T;T;T;T;T
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.88	P;P;P;P;.
Vest4		0.62
MutPred		0.79		Gain of methylation at K471 (P = 0.0774);Gain of methylation at K471 (P = 0.0774);Gain of methylation at K471 (P = 0.0774);.;.;
MVP		0.32
MPC		0.12
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.14
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-92249499;