22-30617432-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.1043C>T(p.Ser348Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,938 control chromosomes in the GnomAD database, including 12,033 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. S348C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1410 hom., cov: 31)

Exomes 𝑓: 0.12 ( 10623 hom. )

Consequence

TCN2
NM_000355.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.01

Publications

41 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=0.002291888).

BP6

Variant 22-30617432-C-T is Benign according to our data. Variant chr22-30617432-C-T is described in ClinVar as Benign. ClinVar VariationId is 341211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.156 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.1043C>T	p.Ser348Phe	missense	Exon 7 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.962C>T	p.Ser321Phe	missense	Exon 7 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.1043C>T	p.Ser348Phe	missense	Exon 7 of 9	ENSP00000215838.3	P20062-1
TCN2	ENST00000407817.3	TSL:1	c.962C>T	p.Ser321Phe	missense	Exon 7 of 9	ENSP00000384914.3	P20062-2
TCN2	ENST00000947107.1		c.1043C>T	p.Ser348Phe	missense	Exon 7 of 10	ENSP00000617166.1

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19728

AN:

151946

Hom.:

1405

Cov.:

show subpopulations

Gnomad AFR

AF:

0.156

Gnomad AMI

AF:

0.0855

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.0810

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.125

GnomAD2 exomes

AF:

0.114

AC:

28589

AN:

251466

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.159

Gnomad AMR exome

AF:

0.149

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.153

Gnomad NFE exome

AF:

0.116

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.117

AC:

170354

AN:

1461874

Hom.:

10623

Cov.:

AF XY:

0.116

AC XY:

84083

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.163

AC:

5468

AN:

33480

American (AMR)

AF:

0.155

AC:

6920

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

2893

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39700

South Asian (SAS)

AF:

0.0830

AC:

7156

AN:

86256

European-Finnish (FIN)

AF:

0.156

AC:

8348

AN:

53416

Middle Eastern (MID)

AF:

0.111

AC:

638

AN:

5768

European-Non Finnish (NFE)

AF:

0.119

AC:

131833

AN:

1112004

Other (OTH)

AF:

0.117

AC:

7090

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

9570

19140

28711

38281

47851

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4814

9628

14442

19256

24070

<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:

0.130

AC:

19756

AN:

152064

Hom.:

1410

Cov.:

AF XY:

0.131

AC XY:

9727

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.156

AC:

6475

AN:

41430

American (AMR)

AF:

0.161

AC:

2460

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

364

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0814

AC:

393

AN:

4826

European-Finnish (FIN)

AF:

0.157

AC:

1660

AN:

10580

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8019

AN:

67986

Other (OTH)

AF:

0.124

AC:

262

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

851

1702

2553

3404

4255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

212

424

636

848

1060

<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:

0.115

Hom.:

3517

Bravo

AF:

0.130

TwinsUK

AF:

0.111

AC:

411

ALSPAC

AF:

0.115

AC:

445

ESP6500AA

AF:

0.153

AC:

676

ESP6500EA

AF:

0.114

AC:

978

ExAC

AF:

0.112

AC:

13584

Asia WGS

AF:

0.0500

AC:

174

AN:

3478

EpiCase

AF:

0.115

EpiControl

AF:

0.114

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Transcobalamin II deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

1.0

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.31

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

-1.0

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.013

Sift

Benign

0.16

Sift4G

Benign

0.12

Polyphen

0.0020

Vest4

0.15

MPC

0.0092

ClinPred

0.0079

GERP RS

-5.3

Varity_R

0.22

gMVP

0.40

Mutation Taster

=75/25

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