14-91802364-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.359A>G(p.His120Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: TC2N NM_001128596.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85

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=0.13212034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TC2N	NM_001128596.3	c.359A>G	p.His120Arg	missense_variant	4/12	ENST00000435962.7
TC2N	NM_001128595.3	c.359A>G	p.His120Arg	missense_variant	4/12
TC2N	NM_152332.6	c.359A>G	p.His120Arg	missense_variant	4/12
TC2N	NM_001289134.2	c.359A>G	p.His120Arg	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TC2N	ENST00000435962.7	c.359A>G	p.His120Arg	missense_variant	4/12	2	NM_001128596.3	P1
TC2N	ENST00000340892.9	c.359A>G	p.His120Arg	missense_variant	4/12	1		P1
TC2N	ENST00000360594.9	c.359A>G	p.His120Arg	missense_variant	4/12	1		P1
TC2N	ENST00000556018.5	c.359A>G	p.His120Arg	missense_variant	4/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Feb 06, 2024

The c.359A>G (p.H120R) 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 359, causing the histidine (H) at amino acid position 120 to be replaced by an arginine (R). 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	0.067
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	11
Dann	Benign	0.96
DEOGEN2	Benign	0.032	T;T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.52	D
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.037
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.028	B;B;B;B
Vest4		0.28
MutPred		0.24		Gain of solvent accessibility (P = 0.0105);Gain of solvent accessibility (P = 0.0105);Gain of solvent accessibility (P = 0.0105);Gain of solvent accessibility (P = 0.0105);
MVP		0.37
MPC		0.056
ClinPred		0.14	T
GERP RS		4.1
Varity_R		0.089
gMVP		0.21

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: chr14-92268708;