22-30617432-C-T

Position:

chr22-30617432-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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:3

Conservation

PhyloP100: -1.01

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCN2	NM_000355.4 linkuse as main transcript	c.1043C>T	p.Ser348Phe	missense_variant	7/9	ENST00000215838.8
TCN2	NM_001184726.2 linkuse as main transcript	c.962C>T	p.Ser321Phe	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000215838.8 linkuse as main transcript	c.1043C>T	p.Ser348Phe	missense_variant	7/9	1	NM_000355.4	P2	P20062-1

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

GnomAD3 exomes

AF:

0.114

AC:

28589

AN:

251466

Hom.:

1841

AF XY:

0.112

AC XY:

15217

AN XY:

135910

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 SAS exome

AF:

0.0825

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

Gnomad4 AFR exome

AF:

0.163

Gnomad4 AMR exome

AF:

0.155

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0830

Gnomad4 FIN exome

AF:

0.156

Gnomad4 NFE exome

AF:

0.119

Gnomad4 OTH exome

AF:

0.117

GnomAD4 genome

AF:

0.130

AC:

19756

AN:

152064

Hom.:

1410

Cov.:

AF XY:

0.131

AC XY:

9727

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.156

Gnomad4 AMR

AF:

0.161

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.0814

Gnomad4 FIN

AF:

0.157

Gnomad4 NFE

AF:

0.118

Gnomad4 OTH

AF:

0.124

Alfa

AF:

0.112

Hom.:

2410

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Transcobalamin II deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

1.0

DANN

Benign

0.68

DEOGEN2

Benign

0.31

T;T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.55

T;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.5

D;.;D;D

REVEL

Benign

0.013

Sift

Benign

0.16

T;.;T;T

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.0020

B;.;B;.

Vest4

0.15

MPC

0.0092

ClinPred

0.0079

GERP RS

-5.3

Varity_R

0.22

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over