Genetic Variant TC2N:p.Thr292Met (chr14-91792539-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001128596.3(TC2N):c.875C>T(p.Thr292Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000645 in 1,549,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

TC2N
NM_001128596.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.96

Publications

3 publications found

Variant links:

Genes affected

TC2N (HGNC:19859): (tandem C2 domains, nuclear) Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TC2N links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TC2N	NM_001128596.3	MANE Select	c.875C>T	p.Thr292Met	missense	Exon 9 of 12	NP_001122068.2	Q8N9U0-1
TC2N	NM_001128595.3		c.875C>T	p.Thr292Met	missense	Exon 9 of 12	NP_001122067.2	Q8N9U0-1
TC2N	NM_152332.6		c.875C>T	p.Thr292Met	missense	Exon 9 of 12	NP_689545.2	Q8N9U0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TC2N	ENST00000435962.7	TSL:2 MANE Select	c.875C>T	p.Thr292Met	missense	Exon 9 of 12	ENSP00000387882.2	Q8N9U0-1
TC2N	ENST00000340892.9	TSL:1	c.875C>T	p.Thr292Met	missense	Exon 9 of 12	ENSP00000343199.5	Q8N9U0-1
TC2N	ENST00000360594.9	TSL:1	c.875C>T	p.Thr292Met	missense	Exon 9 of 12	ENSP00000353802.5	Q8N9U0-1

Frequencies

GnomAD3 genomes

AF:

0.0000399

AC:

AN:

150512

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000886

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000388

AC:

AN:

232052

AF XY:

0.0000398

show subpopulations

Gnomad AFR exome

AF:

0.0000643

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:

0.0000745

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000672

AC:

AN:

1399036

Hom.:

Cov.:

AF XY:

0.0000589

AC XY:

AN XY:

695530

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31652

American (AMR)

AF:

0.00

AC:

AN:

40634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24668

East Asian (EAS)

AF:

0.00

AC:

AN:

39116

South Asian (SAS)

AF:

0.00

AC:

AN:

74852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51502

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

0.0000829

AC:

AN:

1073442

Other (OTH)

AF:

0.0000520

AC:

AN:

57648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000399

AC:

AN:

150512

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40900

American (AMR)

AF:

0.00

AC:

AN:

15124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000886

AC:

AN:

67736

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.4

PhyloP100

8.0

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.79

Loss of catalytic residue at F295 (P = 0.1266)

MVP

0.92

MPC

0.32

ClinPred

0.74

GERP RS

5.7

Varity_R

0.52

gMVP

0.56

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over