22-30623057-G-A

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.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. 15/21 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. R399G) has been classified as Uncertain significance.

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

Publications

18 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=0.0028435886).

BP6

Variant 22-30623057-G-A is Benign according to our data. Variant chr22-30623057-G-A is described in ClinVar as Benign. ClinVar VariationId is 341215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 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.1196G>A	p.Arg399Gln	missense	Exon 8 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.1115G>A	p.Arg372Gln	missense	Exon 8 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.1196G>A	p.Arg399Gln	missense	Exon 8 of 9	ENSP00000215838.3	P20062-1
TCN2	ENST00000407817.3	TSL:1	c.1115G>A	p.Arg372Gln	missense	Exon 8 of 9	ENSP00000384914.3	P20062-2
TCN2	ENST00000947107.1		c.1319G>A	p.Arg440Gln	missense	Exon 9 of 10	ENSP00000617166.1

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

GnomAD2 exomes

AF:

0.0320

AC:

8046

AN:

251458

AF XY:

0.0314

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 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

African (AFR)

AF:

0.106

AC:

3565

AN:

33478

American (AMR)

AF:

0.0207

AC:

927

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

512

AN:

26134

East Asian (EAS)

AF:

0.00159

AC:

AN:

39700

South Asian (SAS)

AF:

0.0440

AC:

3791

AN:

86256

European-Finnish (FIN)

AF:

0.0160

AC:

855

AN:

53416

Middle Eastern (MID)

AF:

0.0505

AC:

291

AN:

5768

European-Non Finnish (NFE)

AF:

0.0281

AC:

31297

AN:

1111992

Other (OTH)

AF:

0.0323

AC:

1948

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2462

4924

7386

9848

12310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1178

2356

3534

4712

5890

<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:

0.0506

AC:

7686

AN:

151890

Hom.:

311

Cov.:

AF XY:

0.0499

AC XY:

3705

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.109

AC:

4496

AN:

41380

American (AMR)

AF:

0.0347

AC:

529

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3466

East Asian (EAS)

AF:

0.00272

AC:

AN:

5152

South Asian (SAS)

AF:

0.0454

AC:

218

AN:

4800

European-Finnish (FIN)

AF:

0.0144

AC:

152

AN:

10572

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0299

AC:

2031

AN:

67972

Other (OTH)

AF:

0.0526

AC:

111

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

347

694

1040

1387

1734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0372

Hom.:

490

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Transcobalamin II deficiency (3)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.86

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.049

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

-0.46

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.68

REVEL

Benign

0.028

Sift

Benign

0.15

Sift4G

Benign

0.10

Polyphen

0.23

Vest4

0.063

MPC

0.0091

ClinPred

0.0020

GERP RS

2.1

Varity_R

0.14

gMVP

0.60

Mutation Taster

=97/3

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