22-30607151-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000450638.5(TCN2):c.-357A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 658,624 control chromosomes in the GnomAD database, including 108,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31863 hom., cov: 29)
  • Exomes 𝑓: 0.54 (77078 hom.)
• Consequence: TCN2 ENST00000450638.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.802

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 22-30607151-A-G is Benign according to our data. Variant chr22-30607151-A-G is described in ClinVar as [Benign]. Clinvar id is 341183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCN2	NM_000355.4			upstream_gene_variant		ENST00000215838.8
TCN2	NM_001184726.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000215838.8			upstream_gene_variant		1	NM_000355.4	P2

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96039 AN: 151394 Hom.: 31826 Cov.: 29

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.619

GnomAD4 exome AF: 0.536 AC: 271744 AN: 507116 Hom.: 77078 Cov.: 6 AF XY: 0.527 AC XY: 141705 AN XY: 268870

Gnomad4 AFR exome AF: 0.821

Gnomad4 AMR exome AF: 0.520

Gnomad4 ASJ exome AF: 0.564

Gnomad4 EAS exome AF: 0.243

Gnomad4 SAS exome AF: 0.390

Gnomad4 FIN exome AF: 0.604

Gnomad4 NFE exome AF: 0.569

Gnomad4 OTH exome AF: 0.561

GnomAD4 genome AF: 0.634 AC: 96129 AN: 151508 Hom.: 31863 Cov.: 29 AF XY: 0.630 AC XY: 46621 AN XY: 73998

Gnomad4 AFR AF: 0.822

Gnomad4 AMR AF: 0.581

Gnomad4 ASJ AF: 0.565

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.613

Gnomad4 NFE AF: 0.585

Gnomad4 OTH AF: 0.615

Alfa AF: 0.594 Hom.: 8299

Bravo AF: 0.638

Asia WGS AF: 0.394 AC: 1376 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Transcobalamin II deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	13
Dann	Benign	0.77

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: rs2240433; hg19: chr22-31003138;