rs2301955

Variant names:

• chr22-30622659-C-T
• rs2301955
• NM_000355.4:c.1107-309C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000355.4(TCN2):​c.1107-309C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 151,984 control chromosomes in the GnomAD database, including 10,073 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.35 (10073 hom., cov: 32)
• Consequence: TCN2 NM_000355.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.22
• Publications: 6 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: PanelApp Australia, ClinGen, Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 22-30622659-C-T is Benign according to our data. Variant chr22-30622659-C-T is described in ClinVar as Benign. ClinVar VariationId is 1227845.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000355.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	NM_000355.4	MANE Select	c.1107-309C>T		intron	N/A	NP_000346.2
	TCN2	NM_001184726.2		c.1026-309C>T		intron	N/A	NP_001171655.1	P20062-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	ENST00000215838.8	TSL:1 MANE Select	c.1107-309C>T		intron	N/A	ENSP00000215838.3	P20062-1
	TCN2	ENST00000407817.3	TSL:1	c.1026-309C>T		intron	N/A	ENSP00000384914.3	P20062-2
	TCN2	ENST00000947107.1		c.1230-309C>T		intron	N/A	ENSP00000617166.1

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53940 AN: 151864 Hom.: 10071 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.370

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.355 AC: 53945 AN: 151984 Hom.: 10073 Cov.: 32 AF XY: 0.353 AC XY: 26232 AN XY: 74292

African (AFR) AF: 0.251 AC: 10384 AN: 41448

American (AMR) AF: 0.343 AC: 5236 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1548 AN: 3466

East Asian (EAS) AF: 0.194 AC: 1004 AN: 5180

South Asian (SAS) AF: 0.266 AC: 1280 AN: 4816

European-Finnish (FIN) AF: 0.449 AC: 4737 AN: 10546

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28461 AN: 67936

Other (OTH) AF: 0.365 AC: 771 AN: 2112

Alfa AF: 0.403 Hom.: 8010

Bravo AF: 0.343

Asia WGS AF: 0.262 AC: 914 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.61
DANN	Benign	0.40
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2301955; hg19: chr22-31018646;