22-30615623-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000355.4(TCN2):c.776G>C(p.Arg259Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,732 control chromosomes in the GnomAD database, including 258,781 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 29857 hom., cov: 32)

Exomes 𝑓: 0.56 ( 228924 hom. )

Consequence

TCN2
NM_000355.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.373

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4999782E-6).

BP6

Variant 22-30615623-G-C is Benign according to our data. Variant chr22-30615623-G-C is described in ClinVar as [Benign]. Clinvar id is 97.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30615623-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4 link	c.776G>C	p.Arg259Pro	missense_variant	Exon 6 of 9	ENST00000215838.8	NP_000346.2	P20062-1
TCN2	NM_001184726.2 link	c.695G>C	p.Arg232Pro	missense_variant	Exon 6 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.776G>C	p.Arg259Pro	missense_variant	Exon 6 of 9	1	NM_000355.4	ENSP00000215838.3		P20062-1

Frequencies

GnomAD3 genomes

AF:

0.620

AC:

94100

AN:

151870

Hom.:

29826

Cov.:

show subpopulations

Gnomad AFR

AF:

0.759

Gnomad AMI

AF:

0.576

Gnomad AMR

AF:

0.646

Gnomad ASJ

AF:

0.583

Gnomad EAS

AF:

0.441

Gnomad SAS

AF:

0.408

Gnomad FIN

AF:

0.634

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.558

Gnomad OTH

AF:

0.602

GnomAD3 exomes

AF:

0.569

AC:

142938

AN:

251026

Hom.:

42003

AF XY:

0.559

AC XY:

75819

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.764

Gnomad AMR exome

AF:

0.666

Gnomad ASJ exome

AF:

0.591

Gnomad EAS exome

AF:

0.428

Gnomad SAS exome

AF:

0.414

Gnomad FIN exome

AF:

0.635

Gnomad NFE exome

AF:

0.562

Gnomad OTH exome

AF:

0.578

GnomAD4 exome

AF:

0.556

AC:

812000

AN:

1461744

Hom.:

228924

Cov.:

AF XY:

0.551

AC XY:

400881

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.780

Gnomad4 AMR exome

AF:

0.663

Gnomad4 ASJ exome

AF:

0.586

Gnomad4 EAS exome

AF:

0.445

Gnomad4 SAS exome

AF:

0.419

Gnomad4 FIN exome

AF:

0.635

Gnomad4 NFE exome

AF:

0.554

Gnomad4 OTH exome

AF:

0.566

GnomAD4 genome

AF:

0.620

AC:

94182

AN:

151988

Hom.:

29857

Cov.:

AF XY:

0.618

AC XY:

45900

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.759

Gnomad4 AMR

AF:

0.646

Gnomad4 ASJ

AF:

0.583

Gnomad4 EAS

AF:

0.441

Gnomad4 SAS

AF:

0.408

Gnomad4 FIN

AF:

0.634

Gnomad4 NFE

AF:

0.559

Gnomad4 OTH

AF:

0.595

Alfa

AF:

0.535

Hom.:

5859

Bravo

AF:

0.628

TwinsUK

AF:

0.555

AC:

2057

ALSPAC

AF:

0.551

AC:

2125

ESP6500AA

AF:

0.765

AC:

3372

ESP6500EA

AF:

0.566

AC:

4865

ExAC

AF:

0.567

AC:

68821

Asia WGS

AF:

0.467

AC:

1627

AN:

3478

EpiCase

AF:

0.566

EpiControl

AF:

0.574

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Transcobalamin II deficiency

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2Other:1

Jul 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12091374, 21975197, 14680986, 19353223, 12107818, 19936946, 22794911, 23099805) -

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. -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

TCN2 POLYMORPHISM

Benign:1

Jun 01, 2007

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.5

DANN

Benign

0.25

DEOGEN2

Benign

0.019

T;T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.29

T;T;T;T

MetaRNN

Benign

0.0000015

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.5

N;.;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

1.3

N;.;N;N

REVEL

Benign

0.11

Sift

Benign

1.0

T;.;T;T

Sift4G

Benign

0.59

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.050

MPC

0.0087

ClinPred

0.0088

GERP RS

4.1

Varity_R

0.42

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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