chr14-91785245-G-T

Variant names:

• chr14-91785245-G-T
• rs201731267
• NM_001128596.3:c.1279C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001128596.3(TC2N):​c.1279C>A​(p.Leu427Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L427F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TC2N NM_001128596.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09302357).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128596.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TC2N	NM_001128596.3	MANE Select	c.1279C>A	p.Leu427Ile	missense	Exon 11 of 12	NP_001122068.2	Q8N9U0-1
	TC2N	NM_001128595.3		c.1279C>A	p.Leu427Ile	missense	Exon 11 of 12	NP_001122067.2	Q8N9U0-1
	TC2N	NM_152332.6		c.1279C>A	p.Leu427Ile	missense	Exon 11 of 12	NP_689545.2	Q8N9U0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TC2N	ENST00000435962.7	TSL:2 MANE Select	c.1279C>A	p.Leu427Ile	missense	Exon 11 of 12	ENSP00000387882.2	Q8N9U0-1
	TC2N	ENST00000340892.9	TSL:1	c.1279C>A	p.Leu427Ile	missense	Exon 11 of 12	ENSP00000343199.5	Q8N9U0-1
	TC2N	ENST00000360594.9	TSL:1	c.1279C>A	p.Leu427Ile	missense	Exon 11 of 12	ENSP00000353802.5	Q8N9U0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460830 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726764

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111178

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.71
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.060
Sift	Benign	0.79	T
Sift4G	Benign	0.37	T
Polyphen		0.43	B
Vest4		0.25
MutPred		0.40		Loss of ubiquitination at K432 (P = 0.1)
MVP		0.26
MPC		0.065
ClinPred		0.59	D
GERP RS		3.2
Varity_R		0.044
gMVP		0.15
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs201731267; hg19: chr14-92251589;