NM_000355.4:c.776G>C

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.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. 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. R259C) has been classified as Uncertain significance.

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

Publications

227 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=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 VariationId is 97.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.752 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.776G>C	p.Arg259Pro	missense	Exon 6 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.695G>C	p.Arg232Pro	missense	Exon 6 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.776G>C	p.Arg259Pro	missense	Exon 6 of 9	ENSP00000215838.3	P20062-1
TCN2	ENST00000407817.3	TSL:1	c.695G>C	p.Arg232Pro	missense	Exon 6 of 9	ENSP00000384914.3	P20062-2
TCN2	ENST00000947107.1		c.776G>C	p.Arg259Pro	missense	Exon 6 of 10	ENSP00000617166.1

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

GnomAD2 exomes

AF:

0.569

AC:

142938

AN:

251026

AF XY:

0.559

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 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

African (AFR)

AF:

0.780

AC:

26098

AN:

33480

American (AMR)

AF:

0.663

AC:

29649

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.586

AC:

15312

AN:

26134

East Asian (EAS)

AF:

0.445

AC:

17669

AN:

39698

South Asian (SAS)

AF:

0.419

AC:

36109

AN:

86254

European-Finnish (FIN)

AF:

0.635

AC:

33876

AN:

53368

Middle Eastern (MID)

AF:

0.545

AC:

3141

AN:

5768

European-Non Finnish (NFE)

AF:

0.554

AC:

615949

AN:

1111934

Other (OTH)

AF:

0.566

AC:

34197

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

22738

45477

68215

90954

113692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17292

34584

51876

69168

86460

<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:

0.620

AC:

94182

AN:

151988

Hom.:

29857

Cov.:

AF XY:

0.618

AC XY:

45900

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.759

AC:

31493

AN:

41486

American (AMR)

AF:

0.646

AC:

9856

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.583

AC:

2021

AN:

3464

East Asian (EAS)

AF:

0.441

AC:

2269

AN:

5150

South Asian (SAS)

AF:

0.408

AC:

1963

AN:

4814

European-Finnish (FIN)

AF:

0.634

AC:

6690

AN:

10554

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.559

AC:

37960

AN:

67960

Other (OTH)

AF:

0.595

AC:

1254

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1817

3633

5450

7266

9083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

760

1520

2280

3040

3800

<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:

0.535

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Transcobalamin II deficiency (5)

not provided (3)

not specified (1)

TCN2 POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.5

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.019

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0000015

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.5

PhyloP100

0.37

PrimateAI

Benign

0.28

PROVEAN

Benign

1.3

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

0.59

Polyphen

0.0

Vest4

0.050

MPC

0.0087

ClinPred

0.0088

GERP RS

4.1

Varity_R

0.42

gMVP

0.42

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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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