rs1209227263

Variant names:

• chr14-91792447-C-T
• rs1209227263
• NM_001128596.3:c.967G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_001128596.3(TC2N):​c.967G>A​(p.Glu323Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,150 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (1 hom.)
• Consequence: TC2N NM_001128596.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.19

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29056978).
• BP6: Variant 14-91792447-C-T is Benign according to our data. Variant chr14-91792447-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3453961.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TC2N	NM_001128596.3	c.967G>A	p.Glu323Lys	missense_variant	Exon 9 of 12	ENST00000435962.7	NP_001122068.2
TC2N	NM_001128595.3	c.967G>A	p.Glu323Lys	missense_variant	Exon 9 of 12		NP_001122067.2
TC2N	NM_152332.6	c.967G>A	p.Glu323Lys	missense_variant	Exon 9 of 12		NP_689545.2
TC2N	NM_001289134.2	c.856-4820G>A		intron_variant	Intron 8 of 10		NP_001276063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TC2N	ENST00000435962.7	c.967G>A	p.Glu323Lys	missense_variant	Exon 9 of 12	2	NM_001128596.3	ENSP00000387882.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459150 Hom.: 1 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725888

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 01, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	M;M;M;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Benign	0.22
Sift	Benign	0.041	D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		0.013	B;B;B;.
Vest4		0.37
MutPred		0.57		Gain of MoRF binding (P = 0.0018);Gain of MoRF binding (P = 0.0018);Gain of MoRF binding (P = 0.0018);.;
MVP		0.66
MPC		0.074
ClinPred		0.96	D
GERP RS		2.8
Varity_R		0.23
gMVP		0.70

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

Other links and lift over

dbSNP: rs1209227263; hg19: chr14-92258791;