rs76802001

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000355.4(TCN2):c.1023G>A(p.Pro341Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,614,028 control chromosomes in the GnomAD database, including 957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 65 hom., cov: 31)

Exomes 𝑓: 0.032 ( 892 hom. )

Consequence

TCN2
NM_000355.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.94

Publications

9 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 22-30617412-G-A is Benign according to our data. Variant chr22-30617412-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 341210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.94 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0246 (3744/152158) while in subpopulation AMR AF = 0.039 (596/15268). AF 95% confidence interval is 0.0364. There are 65 homozygotes in GnomAd4. There are 1771 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 65 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4 link	c.1023G>A	p.Pro341Pro	synonymous_variant	Exon 7 of 9	ENST00000215838.8	NP_000346.2	P20062-1
TCN2	NM_001184726.2 link	c.942G>A	p.Pro314Pro	synonymous_variant	Exon 7 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.1023G>A	p.Pro341Pro	synonymous_variant	Exon 7 of 9	1	NM_000355.4	ENSP00000215838.3		P20062-1

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3743

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00708

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0390

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.0218

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0358

Gnomad OTH

AF:

0.0297

GnomAD2 exomes

AF:

0.0253

AC:

6366

AN:

251470

AF XY:

0.0255

show subpopulations

Gnomad AFR exome

AF:

0.00701

Gnomad AMR exome

AF:

0.0296

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0221

Gnomad NFE exome

AF:

0.0362

Gnomad OTH exome

AF:

0.0336

GnomAD4 exome

AF:

0.0319

AC:

46561

AN:

1461870

Hom.:

892

Cov.:

AF XY:

0.0313

AC XY:

22735

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00606

AC:

203

AN:

33480

American (AMR)

AF:

0.0315

AC:

1410

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0128

AC:

334

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00982

AC:

847

AN:

86256

European-Finnish (FIN)

AF:

0.0222

AC:

1186

AN:

53410

Middle Eastern (MID)

AF:

0.0357

AC:

206

AN:

5768

European-Non Finnish (NFE)

AF:

0.0364

AC:

40477

AN:

1112004

Other (OTH)

AF:

0.0314

AC:

1895

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

2910

5820

8729

11639

14549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1460

2920

4380

5840

7300

<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:

0.0246

AC:

3744

AN:

152158

Hom.:

Cov.:

AF XY:

0.0238

AC XY:

1771

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00706

AC:

293

AN:

41512

American (AMR)

AF:

0.0390

AC:

596

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3470

East Asian (EAS)

AF:

0.000773

AC:

AN:

5176

South Asian (SAS)

AF:

0.00892

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0218

AC:

231

AN:

10600

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0358

AC:

2435

AN:

67992

Other (OTH)

AF:

0.0294

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

183

366

550

733

916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0265

Hom.:

Bravo

AF:

0.0256

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0374

EpiControl

AF:

0.0376

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 14, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Transcobalamin II deficiency

Benign:2

Jan 13, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.23

(source)

DANN

Benign

0.54

PhyloP100

-1.9

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over