rs4820889

Positions:

Variant summary

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

The NM_000355.4(TCN2):c.1196G>A(p.Arg399Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,613,750 control chromosomes in the GnomAD database, including 1,183 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 0.051 ( 311 hom., cov: 30)

Exomes 𝑓: 0.030 ( 872 hom. )

Consequence

TCN2
NM_000355.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.457

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028435886).

BP6

Variant 22-30623057-G-A is Benign according to our data. Variant chr22-30623057-G-A is described in ClinVar as [Benign]. Clinvar id is 341215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30623057-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCN2	NM_000355.4 linkuse as main transcript	c.1196G>A	p.Arg399Gln	missense_variant	8/9	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2 linkuse as main transcript	c.1115G>A	p.Arg372Gln	missense_variant	8/9		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8 linkuse as main transcript	c.1196G>A	p.Arg399Gln	missense_variant	8/9	1	NM_000355.4	ENSP00000215838	P2	P20062-1

Frequencies

GnomAD3 genomes

AF:

0.0505

AC:

7658

AN:

151772

Hom.:

306

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.0440

Gnomad AMR

AF:

0.0348

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00271

Gnomad SAS

AF:

0.0454

Gnomad FIN

AF:

0.0144

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0299

Gnomad OTH

AF:

0.0532

GnomAD3 exomes

AF:

0.0320

AC:

8046

AN:

251458

Hom.:

219

AF XY:

0.0314

AC XY:

4265

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.0208

Gnomad ASJ exome

AF:

0.0195

Gnomad EAS exome

AF:

0.00217

Gnomad SAS exome

AF:

0.0425

Gnomad FIN exome

AF:

0.0164

Gnomad NFE exome

AF:

0.0303

Gnomad OTH exome

AF:

0.0274

GnomAD4 exome

AF:

0.0296

AC:

43249

AN:

1461860

Hom.:

872

Cov.:

AF XY:

0.0299

AC XY:

21758

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.106

Gnomad4 AMR exome

AF:

0.0207

Gnomad4 ASJ exome

AF:

0.0196

Gnomad4 EAS exome

AF:

0.00159

Gnomad4 SAS exome

AF:

0.0440

Gnomad4 FIN exome

AF:

0.0160

Gnomad4 NFE exome

AF:

0.0281

Gnomad4 OTH exome

AF:

0.0323

GnomAD4 genome

AF:

0.0506

AC:

7686

AN:

151890

Hom.:

311

Cov.:

AF XY:

0.0499

AC XY:

3705

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.109

Gnomad4 AMR

AF:

0.0347

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.00272

Gnomad4 SAS

AF:

0.0454

Gnomad4 FIN

AF:

0.0144

Gnomad4 NFE

AF:

0.0299

Gnomad4 OTH

AF:

0.0526

Alfa

AF:

0.0349

Hom.:

209

Bravo

AF:

0.0529

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0278

AC:

107

ESP6500AA

AF:

0.0994

AC:

438

ESP6500EA

AF:

0.0295

AC:

254

ExAC

AF:

0.0351

AC:

4262

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0291

EpiControl

AF:

0.0290

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Transcobalamin II deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2019	This variant is associated with the following publications: (PMID: 12107818, 25525159) -

not specified

Benign:1

Benign, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

May 31, 2018

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >10% in African population in Exome Aggregation Consortium. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.86

DANN

Benign

0.96

DEOGEN2

Benign

0.049

T;T;T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.71

T;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.;.;.

MutationTaster

Benign

0.60

P;P;P

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.68

N;.;N;N

REVEL

Benign

0.028

Sift

Benign

0.15

T;.;T;T

Sift4G

Benign

0.10

T;T;T;T

Polyphen

0.23

B;.;B;.

Vest4

0.063

MPC

0.0091

ClinPred

0.0020

GERP RS

2.1

Varity_R

0.14

gMVP

0.60

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

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