22-30626965-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000355.4(TCN2):c.*444C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 268,302 control chromosomes in the GnomAD database, including 8,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5447 hom., cov: 34)
  • Exomes 𝑓: 0.23 (3340 hom.)
• Consequence: TCN2 NM_000355.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.308

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-30626965-C-T is Benign according to our data. Variant chr22-30626965-C-T is described in ClinVar as [Benign]. Clinvar id is 341226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCN2	NM_000355.4	c.*444C>T		3_prime_UTR_variant	9/9	ENST00000215838.8
TCN2	NM_001184726.2	c.*444C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000215838.8	c.*444C>T		3_prime_UTR_variant	9/9	1	NM_000355.4	P2

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39859 AN: 152116 Hom.: 5443 Cov.: 34

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.234 AC: 27215 AN: 116066 Hom.: 3340 Cov.: 0 AF XY: 0.230 AC XY: 14122 AN XY: 61280

Gnomad4 AFR exome AF: 0.340

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.191

Gnomad4 SAS exome AF: 0.211

Gnomad4 FIN exome AF: 0.279

Gnomad4 NFE exome AF: 0.236

Gnomad4 OTH exome AF: 0.246

GnomAD4 genome AF: 0.262 AC: 39879 AN: 152236 Hom.: 5447 Cov.: 34 AF XY: 0.261 AC XY: 19405 AN XY: 74426

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.237

Alfa AF: 0.227 Hom.: 5091

Bravo AF: 0.259

Asia WGS AF: 0.242 AC: 843 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Transcobalamin II deficiency Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	2.3
Dann	Benign	0.44

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: rs10418; hg19: chr22-31022952;