rs35915865

Positions:

chr22-30612880-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000355.4(TCN2):c.265T>C(p.Phe89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,613,682 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. F89F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 32)

Exomes 𝑓: 0.017 ( 254 hom. )

Consequence

TCN2
NM_000355.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -2.59

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035916865).

BP6

Variant 22-30612880-T-C is Benign according to our data. Variant chr22-30612880-T-C is described in ClinVar as [Benign]. Clinvar id is 341191.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 = 0.013 (1984/152324) while in subpopulation NFE AF= 0.0197 (1343/68034). AF 95% confidence interval is 0.0189. There are 24 homozygotes in gnomad4. There are 955 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCN2	NM_000355.4 linkuse as main transcript	c.265T>C	p.Phe89Leu	missense_variant	3/9	ENST00000215838.8
TCN2	NM_001184726.2 linkuse as main transcript	c.265T>C	p.Phe89Leu	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000215838.8 linkuse as main transcript	c.265T>C	p.Phe89Leu	missense_variant	3/9	1	NM_000355.4	P2	P20062-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1985

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.00715

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0197

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0133

AC:

3340

AN:

251270

Hom.:

AF XY:

0.0133

AC XY:

1810

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.00755

Gnomad ASJ exome

AF:

0.00903

Gnomad EAS exome

AF:

0.00218

Gnomad SAS exome

AF:

0.0129

Gnomad FIN exome

AF:

0.00871

Gnomad NFE exome

AF:

0.0196

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0168

AC:

24484

AN:

1461358

Hom.:

254

Cov.:

AF XY:

0.0168

AC XY:

12198

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.00278

Gnomad4 AMR exome

AF:

0.00736

Gnomad4 ASJ exome

AF:

0.00957

Gnomad4 EAS exome

AF:

0.00151

Gnomad4 SAS exome

AF:

0.0139

Gnomad4 FIN exome

AF:

0.00864

Gnomad4 NFE exome

AF:

0.0191

Gnomad4 OTH exome

AF:

0.0144

GnomAD4 genome

AF:

0.0130

AC:

1984

AN:

152324

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

955

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00366

Gnomad4 AMR

AF:

0.0139

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.0153

Gnomad4 FIN

AF:

0.00715

Gnomad4 NFE

AF:

0.0197

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0179

Hom.:

Bravo

AF:

0.0120

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0191

AC:

164

ExAC

AF:

0.0139

AC:

1691

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0161

EpiControl

AF:

0.0172

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Transcobalamin II deficiency

Benign:3

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	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.025

DANN

Benign

0.55

DEOGEN2

Benign

0.025

T;T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.21

T;T;T

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.64

N;.;N

REVEL

Benign

0.023

Sift

Benign

0.82

T;.;T

Sift4G

Benign

0.66

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.091

MutPred

0.24

Loss of catalytic residue at F89 (P = 0.0087);.;Loss of catalytic residue at F89 (P = 0.0087);

MPC

0.0090

ClinPred

0.00087

GERP RS

-8.7

Varity_R

0.043

gMVP

0.14

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

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