14-91797786-T-C

Variant names:

• chr14-91797786-T-C
• rs572770511
• NM_001128596.3:c.854A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001128596.3(TC2N):​c.854A>G​(p.Asn285Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000495 in 1,575,570 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (1 hom.)
• Consequence: TC2N NM_001128596.3 missense, splice_region
• Scores: Splicing: ADA: 0.03586
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.92
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009287566).

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.854A>G	p.Asn285Ser	missense splice_region	Exon 8 of 12	NP_001122068.2	Q8N9U0-1
	TC2N	NM_001128595.3		c.854A>G	p.Asn285Ser	missense splice_region	Exon 8 of 12	NP_001122067.2	Q8N9U0-1
	TC2N	NM_152332.6		c.854A>G	p.Asn285Ser	missense splice_region	Exon 8 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.854A>G	p.Asn285Ser	missense splice_region	Exon 8 of 12	ENSP00000387882.2	Q8N9U0-1
	TC2N	ENST00000340892.9	TSL:1	c.854A>G	p.Asn285Ser	missense splice_region	Exon 8 of 12	ENSP00000343199.5	Q8N9U0-1
	TC2N	ENST00000360594.9	TSL:1	c.854A>G	p.Asn285Ser	missense splice_region	Exon 8 of 12	ENSP00000353802.5	Q8N9U0-1

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151514 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000821 AC: 19 AN: 231508 AF XY: 0.0000719

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000506 AC: 72 AN: 1423944 Hom.: 1 Cov.: 29 AF XY: 0.0000606 AC XY: 43 AN XY: 708994

African (AFR) AF: 0.00 AC: 0 AN: 31446

American (AMR) AF: 0.00 AC: 0 AN: 40186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 39102

South Asian (SAS) AF: 0.000758 AC: 61 AN: 80442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1089182

Other (OTH) AF: 0.000119 AC: 7 AN: 59052

GnomAD4 genome AF: 0.0000396 AC: 6 AN: 151626 Hom.: 1 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74074

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67754

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000509 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.47
DANN	Benign	0.46
DEOGEN2	Benign	0.032	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.036	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.035	N
PhyloP100		-1.9
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.034
Sift	Benign	0.13	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.29		Gain of disorder (P = 0.0588)
MVP		0.29
MPC		0.040
ClinPred		0.011	T
GERP RS		-3.9
Varity_R		0.037
gMVP		0.13
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.036
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.030		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: rs572770511; hg19: chr14-92264130;