rs2283873

Variant names:

• chr22-30617309-G-A
• rs2283873
• NM_000355.4:c.941-21G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000355.4(TCN2):​c.941-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,613,756 control chromosomes in the GnomAD database, including 6,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2288 hom., cov: 31)
  • Exomes 𝑓: 0.042 (4573 hom.)
• Consequence: TCN2 NM_000355.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.274
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• transcobalamin II deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-30617309-G-A is Benign according to our data. Variant chr22-30617309-G-A is described in ClinVar as Benign. ClinVar VariationId is 1222428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.941-21G>A		intron_variant	Intron 6 of 8	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.860-21G>A		intron_variant	Intron 6 of 8		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.941-21G>A		intron_variant	Intron 6 of 8	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18115 AN: 151992 Hom.: 2280 Cov.: 31

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.0600

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0914

GnomAD2 exomes AF: 0.0882 AC: 22156 AN: 251262 AF XY: 0.0773

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.239

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0520

GnomAD4 exome AF: 0.0423 AC: 61776 AN: 1461646 Hom.: 4573 Cov.: 31 AF XY: 0.0415 AC XY: 30162 AN XY: 727136

African (AFR) AF: 0.316 AC: 10565 AN: 33466

American (AMR) AF: 0.195 AC: 8727 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 746 AN: 26126

East Asian (EAS) AF: 0.248 AC: 9859 AN: 39680

South Asian (SAS) AF: 0.0666 AC: 5746 AN: 86236

European-Finnish (FIN) AF: 0.0248 AC: 1322 AN: 53374

Middle Eastern (MID) AF: 0.0641 AC: 370 AN: 5768

European-Non Finnish (NFE) AF: 0.0188 AC: 20887 AN: 1111902

Other (OTH) AF: 0.0589 AC: 3554 AN: 60382

GnomAD4 genome AF: 0.119 AC: 18160 AN: 152110 Hom.: 2288 Cov.: 31 AF XY: 0.119 AC XY: 8868 AN XY: 74374

African (AFR) AF: 0.303 AC: 12546 AN: 41448

American (AMR) AF: 0.134 AC: 2054 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3472

East Asian (EAS) AF: 0.245 AC: 1265 AN: 5172

South Asian (SAS) AF: 0.0598 AC: 288 AN: 4816

European-Finnish (FIN) AF: 0.0267 AC: 283 AN: 10610

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.0204 AC: 1384 AN: 67996

Other (OTH) AF: 0.0914 AC: 193 AN: 2112

Alfa AF: 0.0562 Hom.: 2614

Bravo AF: 0.138

Asia WGS AF: 0.150 AC: 524 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Transcobalamin II deficiency Benign:1

Dec 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.1
DANN	Benign	0.92
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2283873; hg19: chr22-31013296; COSMIC: COSV53190910;