NM_000355.4:c.265T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000355.4(TCN2):c.265T>C(p.Phe89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,613,682 control chromosomes in the GnomAD database, including 278 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. F89F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 32)

Exomes 𝑓: 0.017 ( 254 hom. )

Consequence

TCN2
NM_000355.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: -2.59

Publications

7 publications found

Variant links:

Genes affected

TCN2 (HGNC:11653): (transcobalamin 2) This gene encodes a member of the vitamin B12-binding protein family. This family of proteins, alternatively referred to as R binders, is expressed in various tissues and secretions. This plasma protein binds cobalamin and mediates the transport of cobalamin into cells. This protein and other mammalian cobalamin-binding proteins, such as transcobalamin I and gastric intrisic factor, may have evolved by duplication of a common ancestral gene. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

TCN2 Gene-Disease associations (from GenCC):

transcobalamin II deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

TCN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035916865).

BP6

Variant 22-30612880-T-C is Benign according to our data. Variant chr22-30612880-T-C is described in ClinVar as Benign. ClinVar VariationId is 341191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.013 (1984/152324) while in subpopulation NFE AF = 0.0197 (1343/68034). AF 95% confidence interval is 0.0189. There are 24 homozygotes in GnomAd4. There are 955 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4 link	c.265T>C	p.Phe89Leu	missense_variant	Exon 3 of 9	ENST00000215838.8	NP_000346.2	P20062-1
TCN2	NM_001184726.2 link	c.265T>C	p.Phe89Leu	missense_variant	Exon 3 of 9		NP_001171655.1	P20062-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8 link	c.265T>C	p.Phe89Leu	missense_variant	Exon 3 of 9	1	NM_000355.4	ENSP00000215838.3		P20062-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1985

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.00715

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0197

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0133

AC:

3340

AN:

251270

AF XY:

0.0133

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.00755

Gnomad ASJ exome

AF:

0.00903

Gnomad EAS exome

AF:

0.00218

Gnomad FIN exome

AF:

0.00871

Gnomad NFE exome

AF:

0.0196

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0168

AC:

24484

AN:

1461358

Hom.:

254

Cov.:

AF XY:

0.0168

AC XY:

12198

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.00278

AC:

AN:

33458

American (AMR)

AF:

0.00736

AC:

329

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00957

AC:

250

AN:

26136

East Asian (EAS)

AF:

0.00151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0139

AC:

1196

AN:

86240

European-Finnish (FIN)

AF:

0.00864

AC:

461

AN:

53380

Middle Eastern (MID)

AF:

0.00722

AC:

AN:

5400

European-Non Finnish (NFE)

AF:

0.0191

AC:

21187

AN:

1111974

Other (OTH)

AF:

0.0144

AC:

869

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1435

2869

4304

5738

7173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

752

1504

2256

3008

3760

<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:

0.0130

AC:

1984

AN:

152324

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

955

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00366

AC:

152

AN:

41574

American (AMR)

AF:

0.0139

AC:

212

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3472

East Asian (EAS)

AF:

0.00232

AC:

AN:

5180

South Asian (SAS)

AF:

0.0153

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00715

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0197

AC:

1343

AN:

68034

Other (OTH)

AF:

0.0156

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

208

313

417

521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0181

Hom.:

Bravo

AF:

0.0120

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0191

AC:

164

ExAC

AF:

0.0139

AC:

1691

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0161

EpiControl

AF:

0.0172

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Transcobalamin II deficiency

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.025

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.025

T;T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.21

T;T;T

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;.;N

PhyloP100

-2.6

PrimateAI

Benign

0.31

PROVEAN

Benign

0.64

N;.;N

REVEL

Benign

0.023

Sift

Benign

0.82

T;.;T

Sift4G

Benign

0.66

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.091

MutPred

0.24

Loss of catalytic residue at F89 (P = 0.0087);.;Loss of catalytic residue at F89 (P = 0.0087);

MPC

0.0090

ClinPred

0.00087

GERP RS

-8.7

Varity_R

0.043

gMVP

0.14

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over