rs45624233

Positions:

• chr22-30615724-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000355.4(TCN2):​c.877C>T​(p.Leu293Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,614,200 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (26 hom.)
• Consequence: TCN2 NM_000355.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.49

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 22-30615724-C-T is Benign according to our data. Variant chr22-30615724-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 341204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30615724-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00334 (509/152306) while in subpopulation NFE AF= 0.00588 (400/68026). AF 95% confidence interval is 0.0054. There are 0 homozygotes in gnomad4. There are 233 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCN2	NM_000355.4	c.877C>T	p.Leu293Leu	synonymous_variant	6/9	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.796C>T	p.Leu266Leu	synonymous_variant	6/9		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.877C>T	p.Leu293Leu	synonymous_variant	6/9	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 509 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00362 AC: 911 AN: 251464 Hom.: 3 AF XY: 0.00330 AC XY: 449 AN XY: 135910

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00573

Gnomad NFE exome AF: 0.00637

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00543 AC: 7935 AN: 1461894 Hom.: 26 Cov.: 35 AF XY: 0.00531 AC XY: 3864 AN XY: 727248

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00627

Gnomad4 NFE exome AF: 0.00656

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00313 AC XY: 233 AN XY: 74482

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00450 Hom.: 4

Bravo AF: 0.00309

EpiCase AF: 0.00474

EpiControl AF: 0.00528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Transcobalamin II deficiency Benign:3

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TCN2: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.6
DANN	Benign	0.78

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: rs45624233; hg19: chr22-31011711;