rs7290898

chr22-30615293-A-Cchr22-30615293-A-Gchr22-30615293-A-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.581-8A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,613,694 control chromosomes in the GnomAD database, including 6,231 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2162 hom., cov: 32)
  • Exomes 𝑓: 0.035 (4069 hom.)
• Consequence: TCN2 NM_000355.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001423
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.71

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=-0.95).
• BP6: Variant 22-30615293-A-C is Benign according to our data. Variant chr22-30615293-A-C is described in ClinVar as [Benign]. Clinvar id is 341199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCN2	NM_000355.4	c.581-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000215838.8
TCN2	NM_001184726.2	c.500-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000215838.8	c.581-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000355.4	P2

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17109 AN: 151780 Hom.: 2154 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.0345

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0857

GnomAD3 exomes AF: 0.0793 AC: 19918 AN: 251190 Hom.: 2094 AF XY: 0.0666 AC XY: 9043 AN XY: 135782

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.0235

Gnomad EAS exome AF: 0.225

Gnomad SAS exome AF: 0.0356

Gnomad FIN exome AF: 0.0241

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0440

GnomAD4 exome AF: 0.0349 AC: 51048 AN: 1461796 Hom.: 4069 Cov.: 32 AF XY: 0.0333 AC XY: 24213 AN XY: 727200

Gnomad4 AFR exome AF: 0.310

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.0262

Gnomad4 EAS exome AF: 0.237

Gnomad4 SAS exome AF: 0.0356

Gnomad4 FIN exome AF: 0.0211

Gnomad4 NFE exome AF: 0.0130

Gnomad4 OTH exome AF: 0.0512

GnomAD4 genome AF: 0.113 AC: 17152 AN: 151898 Hom.: 2162 Cov.: 32 AF XY: 0.112 AC XY: 8345 AN XY: 74212

Gnomad4 AFR AF: 0.298

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.0343

Gnomad4 FIN AF: 0.0222

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.0853

Alfa AF: 0.0503 Hom.: 314

Bravo AF: 0.132

EpiCase AF: 0.0177

EpiControl AF: 0.0170

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Transcobalamin II deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.14
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.010
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: rs7290898; hg19: chr22-31011280; COSMIC: COSV53191563; COSMIC: COSV53191563;