14-91783204-T-A

Variant names:

• chr14-91783204-T-A
• rs766550828
• NM_001128596.3:c.1369A>T

Variant summary

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

The NM_001128596.3(TC2N):​c.1369A>T​(p.Ile457Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,372 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TC2N NM_001128596.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.903

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=0.1329222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TC2N	NM_001128596.3	c.1369A>T	p.Ile457Leu	missense_variant	Exon 12 of 12	ENST00000435962.7	NP_001122068.2
TC2N	NM_001128595.3	c.1369A>T	p.Ile457Leu	missense_variant	Exon 12 of 12		NP_001122067.2
TC2N	NM_152332.6	c.1369A>T	p.Ile457Leu	missense_variant	Exon 12 of 12		NP_689545.2
TC2N	NM_001289134.2	c.1177A>T	p.Ile393Leu	missense_variant	Exon 11 of 11		NP_001276063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TC2N	ENST00000435962.7	c.1369A>T	p.Ile457Leu	missense_variant	Exon 12 of 12	2	NM_001128596.3	ENSP00000387882.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427372 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 712188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.77
DEOGEN2	Benign	0.031	T;T;T;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;L;L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.54	N;N;N;N;N
REVEL	Benign	0.086
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.70	T;T;T;T;T
Polyphen		0.0	B;B;B;B;.
Vest4		0.17
MutPred		0.67		Gain of catalytic residue at I457 (P = 0.0071);Gain of catalytic residue at I457 (P = 0.0071);Gain of catalytic residue at I457 (P = 0.0071);.;.;
MVP		0.16
MPC		0.046
ClinPred		0.28	T
GERP RS		4.4
Varity_R		0.10
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs766550828; hg19: chr14-92249548;