rs201392026

Positions:

chr22-30615656-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting

The NM_000355.4(TCN2):c.809C>T(p.Ala270Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A270T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

TCN2
NM_000355.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.568

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000545 (83/152290) while in subpopulation AMR AF= 0.00177 (27/15292). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCN2	NM_000355.4 linkuse as main transcript	c.809C>T	p.Ala270Val	missense_variant	6/9	ENST00000215838.8
TCN2	NM_001184726.2 linkuse as main transcript	c.728C>T	p.Ala243Val	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000215838.8 linkuse as main transcript	c.809C>T	p.Ala270Val	missense_variant	6/9	1	NM_000355.4	P2	P20062-1

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000442

AC:

111

AN:

251372

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00190

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000457

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000364

AC:

532

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000344

AC XY:

250

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00121

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.000384

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000545

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000441

Hom.:

Bravo

AF:

0.000423

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000387

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Transcobalamin II deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 19, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 270 of the TCN2 protein (p.Ala270Val). This variant is present in population databases (rs201392026, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TCN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 529778). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	TCN2 NM_000355.3 exon 6 p.Ala270Val (c.809C>T): This variant has not been reported in the literature but is present in 0.1% (37/18870) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/22-31011643-C-T). This variant is present in ClinVar (Variation ID:529778). Evolutionary conservation and computational predictive tools for this variant are unclear; of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;T;.

Eigen

Benign

0.075

Eigen_PC

Benign

0.020

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.75

T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;.;.;.

MutationTaster

Benign

0.68

N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

N;.;N;N

REVEL

Benign

0.25

Sift

Benign

0.065

T;.;T;T

Sift4G

Benign

0.097

T;T;T;T

Polyphen

0.96

D;.;D;.

Vest4

0.28

MVP

0.44

MPC

0.023

ClinPred

0.064

GERP RS

5.0

Varity_R

0.23

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.55

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.55

Position offset: -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