22-30615363-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215G) has been classified as Uncertain significance.

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

Publications

16 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: PanelApp Australia, ClinGen, Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

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=0.012358159).

BP6

Variant 22-30615363-C-T is Benign according to our data. Variant chr22-30615363-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000355.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	NM_000355.4	MANE Select	c.643C>T	p.Arg215Trp	missense	Exon 5 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.562C>T	p.Arg188Trp	missense	Exon 5 of 9	NP_001171655.1	P20062-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCN2	ENST00000215838.8	TSL:1 MANE Select	c.643C>T	p.Arg215Trp	missense	Exon 5 of 9	ENSP00000215838.3	P20062-1
TCN2	ENST00000407817.3	TSL:1	c.562C>T	p.Arg188Trp	missense	Exon 5 of 9	ENSP00000384914.3	P20062-2
TCN2	ENST00000947107.1		c.643C>T	p.Arg215Trp	missense	Exon 5 of 10	ENSP00000617166.1

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

GnomAD2 exomes

AF:

0.0249

AC:

6268

AN:

251426

AF XY:

0.0222

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 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

African (AFR)

AF:

0.247

AC:

8266

AN:

33480

American (AMR)

AF:

0.0118

AC:

528

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00241

AC:

AN:

26136

East Asian (EAS)

AF:

0.000630

AC:

AN:

39700

South Asian (SAS)

AF:

0.0317

AC:

2733

AN:

86250

European-Finnish (FIN)

AF:

0.00374

AC:

200

AN:

53408

Middle Eastern (MID)

AF:

0.0312

AC:

180

AN:

5768

European-Non Finnish (NFE)

AF:

0.00595

AC:

6619

AN:

1112010

Other (OTH)

AF:

0.0195

AC:

1176

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1155

2310

3464

4619

5774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

384

768

1152

1536

1920

<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:

0.0718

AC:

10919

AN:

152166

Hom.:

1225

Cov.:

AF XY:

0.0700

AC XY:

5206

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.236

AC:

9787

AN:

41486

American (AMR)

AF:

0.0238

AC:

363

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00213

AC:

AN:

5160

South Asian (SAS)

AF:

0.0278

AC:

134

AN:

4822

European-Finnish (FIN)

AF:

0.00481

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00692

AC:

471

AN:

68018

Other (OTH)

AF:

0.0388

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

433

865

1298

1730

2163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<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:

0.0272

Hom.:

867

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Transcobalamin II deficiency (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.84

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.69

PhyloP100

1.6

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.1

REVEL

Benign

0.15

Sift

Uncertain

0.020

Sift4G

Uncertain

0.026

Polyphen

0.99

Vest4

0.14

MPC

0.032

ClinPred

0.018

GERP RS

5.8

Varity_R

0.11

gMVP

0.48

Mutation Taster

=92/8

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over