rs2072195

Variant names:

• chr22-30626746-A-T
• rs2072195
• NM_000355.4:c.*225A>T

Variant summary

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

The NM_000355.4(TCN2):​c.*225A>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 0.0692 in 613,678 control chromosomes in the GnomAD database, including 4,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2563 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2182 hom.)
• Consequence: TCN2 NM_000355.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.917

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=-0.84).
• BP6: Variant 22-30626746-A-T is Benign according to our data. Variant chr22-30626746-A-T is described in ClinVar as [Benign]. Clinvar id is 341221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.*225A>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.*225A>T		3_prime_UTR_variant	Exon 9 of 9		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.*225A>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18474 AN: 152162 Hom.: 2553 Cov.: 33

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.0220

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0932

GnomAD4 exome AF: 0.0519 AC: 23942 AN: 461396 Hom.: 2182 Cov.: 4 AF XY: 0.0489 AC XY: 11877 AN XY: 243008

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.173

Gnomad4 ASJ exome AF: 0.0252

Gnomad4 EAS exome AF: 0.251

Gnomad4 SAS exome AF: 0.0359

Gnomad4 FIN exome AF: 0.0197

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0603

GnomAD4 genome AF: 0.122 AC: 18515 AN: 152282 Hom.: 2563 Cov.: 33 AF XY: 0.121 AC XY: 9018 AN XY: 74458

Gnomad4 AFR AF: 0.324

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.249

Gnomad4 SAS AF: 0.0354

Gnomad4 FIN AF: 0.0220

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.0926

Alfa AF: 0.0688 Hom.: 171

Bravo AF: 0.142

Asia WGS AF: 0.137 AC: 479 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Transcobalamin II deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.84
CADD	Benign	0.69
DANN	Benign	0.40

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: rs2072195; hg19: chr22-31022733;