rs150225103

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000355.4(TCN2):c.296A>C(p.Lys99Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K99K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

TCN2
NM_000355.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.75

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01659745).

BP6

Variant 22-30612911-A-C is Benign according to our data. Variant chr22-30612911-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529780.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00122 (186/152304) while in subpopulation AFR AF = 0.00404 (168/41566). AF 95% confidence interval is 0.00354. There are 1 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.296A>C	p.Lys99Thr	missense	Exon 3 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.296A>C	p.Lys99Thr	missense	Exon 3 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.296A>C	p.Lys99Thr	missense	Exon 3 of 9	ENSP00000215838.3	P20062-1
TCN2	ENST00000407817.3	TSL:1	c.296A>C	p.Lys99Thr	missense	Exon 3 of 9	ENSP00000384914.3	P20062-2
TCN2	ENST00000947107.1		c.296A>C	p.Lys99Thr	missense	Exon 3 of 10	ENSP00000617166.1

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

184

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00401

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000274

AC:

AN:

251372

AF XY:

0.000206

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000134

AC:

196

AN:

1461826

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00505

AC:

169

AN:

33478

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112008

Other (OTH)

AF:

0.000265

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00122

AC:

186

AN:

152304

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00404

AC:

168

AN:

41566

American (AMR)

AF:

0.000981

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000400

Hom.:

Bravo

AF:

0.00134

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000305

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Transcobalamin II deficiency (3)

not provided (1)

TCN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.66

M_CAP

Benign

0.030

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.81

MutationAssessor

Pathogenic

2.9

PhyloP100

1.8

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.3

REVEL

Benign

0.21

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.49

MVP

0.79

MPC

0.043

ClinPred

0.093

GERP RS

4.4

Varity_R

0.11

gMVP

0.28

Mutation Taster

=84/16

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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