rs1131603

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000355.4(TCN2):c.1127T>C(p.Leu376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,614,044 control chromosomes in the GnomAD database, including 1,756 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 138 hom., cov: 31)

Exomes 𝑓: 0.044 ( 1618 hom. )

Consequence

TCN2
NM_000355.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 2.93

Publications

38 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

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=0.002260387).

BP6

Variant 22-30622988-T-C is Benign according to our data. Variant chr22-30622988-T-C is described in ClinVar as [Benign]. Clinvar id is 341214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0363 (5529/152192) while in subpopulation NFE AF = 0.0498 (3389/67996). AF 95% confidence interval is 0.0484. There are 138 homozygotes in GnomAd4. There are 2713 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 138 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4 link	c.1127T>C	p.Leu376Ser	missense_variant	Exon 8 of 9	ENST00000215838.8	NP_000346.2	P20062-1
TCN2	NM_001184726.2 link	c.1046T>C	p.Leu349Ser	missense_variant	Exon 8 of 9		NP_001171655.1	P20062-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8 link	c.1127T>C	p.Leu376Ser	missense_variant	Exon 8 of 9	1	NM_000355.4	ENSP00000215838.3		P20062-1

Frequencies

GnomAD3 genomes

AF:

0.0363

AC:

5527

AN:

152074

Hom.:

137

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00785

Gnomad AMI

AF:

0.0407

Gnomad AMR

AF:

0.0287

Gnomad ASJ

AF:

0.0472

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0158

Gnomad FIN

AF:

0.0958

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0498

Gnomad OTH

AF:

0.0340

GnomAD2 exomes

AF:

0.0422

AC:

10609

AN:

251480

AF XY:

0.0426

show subpopulations

Gnomad AFR exome

AF:

0.00794

Gnomad AMR exome

AF:

0.0217

Gnomad ASJ exome

AF:

0.0475

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0942

Gnomad NFE exome

AF:

0.0553

Gnomad OTH exome

AF:

0.0492

GnomAD4 exome

AF:

0.0444

AC:

64866

AN:

1461852

Hom.:

1618

Cov.:

AF XY:

0.0444

AC XY:

32302

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00633

AC:

212

AN:

33480

American (AMR)

AF:

0.0224

AC:

1004

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0444

AC:

1160

AN:

26134

East Asian (EAS)

AF:

0.000202

AC:

AN:

39700

South Asian (SAS)

AF:

0.0206

AC:

1781

AN:

86258

European-Finnish (FIN)

AF:

0.0902

AC:

4820

AN:

53416

Middle Eastern (MID)

AF:

0.0433

AC:

250

AN:

5768

European-Non Finnish (NFE)

AF:

0.0478

AC:

53152

AN:

1111980

Other (OTH)

AF:

0.0410

AC:

2479

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3536

7073

10609

14146

17682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0363

AC:

5529

AN:

152192

Hom.:

138

Cov.:

AF XY:

0.0365

AC XY:

2713

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00782

AC:

325

AN:

41536

American (AMR)

AF:

0.0286

AC:

437

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0472

AC:

164

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.0164

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0958

AC:

1017

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0498

AC:

3389

AN:

67996

Other (OTH)

AF:

0.0337

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

275

549

824

1098

1373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0459

Hom.:

705

Bravo

AF:

0.0316

TwinsUK

AF:

0.0442

AC:

164

ALSPAC

AF:

0.0415

AC:

160

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.0501

AC:

431

ExAC

AF:

0.0427

AC:

5180

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0516

EpiControl

AF:

0.0546

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Nov 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28334792, 23754956) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Transcobalamin II deficiency

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

T;T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.66

T;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.;.;.

PhyloP100

2.9

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.69

N;.;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.013

D;.;D;T

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.22

MPC

0.055

ClinPred

0.0060

GERP RS

5.5

Varity_R

0.59

gMVP

0.66

Mutation Taster

=45/55

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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rs1131603

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over