NM_000355.4:c.67A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBA1

The NM_000355.4(TCN2):c.67A>G(p.Ile23Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,613,936 control chromosomes in the GnomAD database, including 12,749 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1488 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11261 hom. )

Consequence

TCN2
NM_000355.4 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0800

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 22-30610873-A-G is Benign according to our data. Variant chr22-30610873-A-G is described in ClinVar as [Benign]. Clinvar id is 341188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4 link	c.67A>G	p.Ile23Val	missense_variant, splice_region_variant	Exon 2 of 9	ENST00000215838.8	NP_000346.2	P20062-1
TCN2	NM_001184726.2 link	c.67A>G	p.Ile23Val	missense_variant, splice_region_variant	Exon 2 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.67A>G	p.Ile23Val	missense_variant, splice_region_variant	Exon 2 of 9	1	NM_000355.4	ENSP00000215838.3		P20062-1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20321

AN:

152050

Hom.:

1478

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.0836

Gnomad EAS

AF:

0.0229

Gnomad SAS

AF:

0.0934

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.118

AC:

29699

AN:

251470

Hom.:

2023

AF XY:

0.116

AC XY:

15751

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.0880

Gnomad EAS exome

AF:

0.0210

Gnomad SAS exome

AF:

0.0976

Gnomad FIN exome

AF:

0.150

Gnomad NFE exome

AF:

0.118

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.121

AC:

176329

AN:

1461768

Hom.:

11261

Cov.:

AF XY:

0.120

AC XY:

87165

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.162

Gnomad4 AMR exome

AF:

0.163

Gnomad4 ASJ exome

AF:

0.0869

Gnomad4 EAS exome

AF:

0.0205

Gnomad4 SAS exome

AF:

0.0982

Gnomad4 FIN exome

AF:

0.152

Gnomad4 NFE exome

AF:

0.123

Gnomad4 OTH exome

AF:

0.116

GnomAD4 genome

AF:

0.134

AC:

20356

AN:

152168

Hom.:

1488

Cov.:

AF XY:

0.135

AC XY:

10050

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.163

Gnomad4 AMR

AF:

0.164

Gnomad4 ASJ

AF:

0.0836

Gnomad4 EAS

AF:

0.0232

Gnomad4 SAS

AF:

0.0934

Gnomad4 FIN

AF:

0.156

Gnomad4 NFE

AF:

0.121

Gnomad4 OTH

AF:

0.132

Alfa

AF:

0.116

Hom.:

2674

Bravo

AF:

0.133

TwinsUK

AF:

0.118

AC:

439

ALSPAC

AF:

0.120

AC:

464

ESP6500AA

AF:

0.154

AC:

678

ESP6500EA

AF:

0.116

AC:

1001

ExAC

AF:

0.117

AC:

14139

Asia WGS

AF:

0.0840

AC:

290

AN:

3478

EpiCase

AF:

0.116

EpiControl

AF:

0.115

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12107818, 21975197, 22102315, 21214274) -

Transcobalamin II deficiency

Benign:2

Mar 06, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.027

T;T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.40

T;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.;L

PrimateAI

Benign

0.44

PROVEAN

Benign

0.010

N;N;N

REVEL

Benign

0.047

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.088

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.088

MPC

0.0099

ClinPred

0.0041

GERP RS

1.3

Varity_R

0.044

gMVP

0.071

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.93

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.93

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over