rs11557600

chr22-30612895-G-Achr22-30612895-G-Cchr22-30612895-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000355.4(TCN2):c.280G>A(p.Gly94Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,613,952 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G94C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (7 hom.)
• Consequence: TCN2 NM_000355.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0400

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038371682).
• BP6: Variant 22-30612895-G-A is Benign according to our data. Variant chr22-30612895-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 440324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30612895-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0021 (320/152308) while in subpopulation AMR AF= 0.0032 (49/15294). AF 95% confidence interval is 0.00273. There are 0 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCN2	NM_000355.4	c.280G>A	p.Gly94Ser	missense_variant	3/9	ENST00000215838.8
TCN2	NM_001184726.2	c.280G>A	p.Gly94Ser	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000215838.8	c.280G>A	p.Gly94Ser	missense_variant	3/9	1	NM_000355.4	P2

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00212 AC: 533 AN: 251304 Hom.: 1 AF XY: 0.00205 AC XY: 279 AN XY: 135862

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00313

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00257 AC: 3761 AN: 1461644 Hom.: 7 Cov.: 32 AF XY: 0.00254 AC XY: 1848 AN XY: 727096

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00689

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74468

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00307

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00286 Hom.: 2

Bravo AF: 0.00241

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00199 AC: 242

EpiCase AF: 0.00344

EpiControl AF: 0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Transcobalamin II deficiency Benign:5

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jun 02, 2017	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	TCN2: BP4 -

TCN2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Aug 15, 2017

BS1, BS2, BP1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, is a missense alteration in a gene for which primarily truncating variants are known to cause disease, and is predicted to be tolerated by multiple functional prediction tools. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.12
Dann	Benign	0.61
DEOGEN2	Benign	0.018	T;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.33	T;T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0038	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.8	N;.;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.2	N;.;N;N
REVEL	Benign	0.018
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.12
MVP		0.055
MPC		0.0092
ClinPred		0.0042	T
GERP RS		1.9
Varity_R		0.017
gMVP		0.12

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

Other links and lift over

dbSNP: rs11557600; hg19: chr22-31008882; COSMIC: COSV105076384; COSMIC: COSV105076384;