22-30615363-C-T

Position:

chr22-30615363-C-T

Variant summary

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

The NM_000355.4(TCN2):c.643C>T(p.Arg215Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,614,038 control chromosomes in the GnomAD database, including 2,419 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 1225 hom., cov: 32)

Exomes 𝑓: 0.014 ( 1194 hom. )

Consequence

TCN2
NM_000355.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.61

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:

TCN2 (HGNC:):

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=0.012358159).

BP6

Variant 22-30615363-C-T is Benign according to our data. Variant chr22-30615363-C-T is described in ClinVar as [Benign]. Clinvar id is 341200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 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.643C>T	p.Arg215Trp	missense_variant	5/9	ENST00000215838.8	NP_000346.2	P20062-1
TCN2	NM_001184726.2 linkuse as main transcript	c.562C>T	p.Arg188Trp	missense_variant	5/9		NP_001171655.1	P20062-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8 linkuse as main transcript	c.643C>T	p.Arg215Trp	missense_variant	5/9	1	NM_000355.4	ENSP00000215838.3		P20062-1

Frequencies

GnomAD3 genomes

AF:

0.0716

AC:

10892

AN:

152048

Hom.:

1221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.236

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0238

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00213

Gnomad SAS

AF:

0.0278

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00692

Gnomad OTH

AF:

0.0387

GnomAD3 exomes

AF:

0.0249

AC:

6268

AN:

251426

Hom.:

518

AF XY:

0.0222

AC XY:

3020

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.243

Gnomad AMR exome

AF:

0.0107

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00130

Gnomad SAS exome

AF:

0.0310

Gnomad FIN exome

AF:

0.00333

Gnomad NFE exome

AF:

0.00710

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.0135

AC:

19790

AN:

1461872

Hom.:

1194

Cov.:

AF XY:

0.0134

AC XY:

9759

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.247

Gnomad4 AMR exome

AF:

0.0118

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.000630

Gnomad4 SAS exome

AF:

0.0317

Gnomad4 FIN exome

AF:

0.00374

Gnomad4 NFE exome

AF:

0.00595

Gnomad4 OTH exome

AF:

0.0195

GnomAD4 genome

AF:

0.0718

AC:

10919

AN:

152166

Hom.:

1225

Cov.:

AF XY:

0.0700

AC XY:

5206

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.236

Gnomad4 AMR

AF:

0.0238

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00213

Gnomad4 SAS

AF:

0.0278

Gnomad4 FIN

AF:

0.00481

Gnomad4 NFE

AF:

0.00692

Gnomad4 OTH

AF:

0.0388

Alfa

AF:

0.0170

Hom.:

354

Bravo

AF:

0.0793

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.237

AC:

1044

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.0298

AC:

3613

Asia WGS

AF:

0.0280

AC:

100

AN:

3478

EpiCase

AF:

0.00845

EpiControl

AF:

0.00936

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Transcobalamin II deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Mendelics	May 28, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	This variant is associated with the following publications: (PMID: 31139930) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

T;T;T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.84

T;T;T;T

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.69

N;.;.;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.1

N;.;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.020

D;.;D;D

Sift4G

Uncertain

0.026

D;D;D;D

Polyphen

0.99

D;.;D;.

Vest4

0.14

MPC

0.032

ClinPred

0.018

GERP RS

5.8

Varity_R

0.11

gMVP

0.48

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