NM_000355.4:c.776G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_000355.4(TCN2):c.776G>A(p.Arg259His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

TCN2
NM_000355.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U: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: 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.059171706).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000246 (36/1461790) while in subpopulation SAS AF = 0.000325 (28/86256). AF 95% confidence interval is 0.00023. There are 0 homozygotes in GnomAdExome4. There are 19 alleles in the male GnomAdExome4 subpopulation. Median coverage is 68. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	NM_000355.4	MANE Select	c.776G>A	p.Arg259His	missense	Exon 6 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.695G>A	p.Arg232His	missense	Exon 6 of 9	NP_001171655.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TCN2	ENST00000215838.8	TSL:1 MANE Select	c.776G>A	p.Arg259His	missense	Exon 6 of 9	ENSP00000215838.3
TCN2	ENST00000407817.3	TSL:1	c.695G>A	p.Arg232His	missense	Exon 6 of 9	ENSP00000384914.3
TCN2	ENST00000947107.1		c.776G>A	p.Arg259His	missense	Exon 6 of 10	ENSP00000617166.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000558

AC:

AN:

251026

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.000325

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111968

Other (OTH)

AF:

0.0000497

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.00000658

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41514

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

5859

ExAC

AF:

0.0000659

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Transcobalamin II deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.036

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.59

M_CAP

Benign

0.012

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.37

PrimateAI

Benign

0.29

PROVEAN

Benign

0.98

REVEL

Benign

0.084

Sift

Benign

0.075

Sift4G

Benign

0.11

Polyphen

0.58

Vest4

0.063

MutPred

0.31

Loss of methylation at R259 (P = 0.0254)

MVP

0.38

MPC

0.014

ClinPred

0.064

GERP RS

4.1

Varity_R

0.071

gMVP

0.28

Mutation Taster

=95/5

polymorphism

(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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over