rs4820887

Variant names:

• chr22-30620927-G-A
• rs4820887
• NM_000355.4:c.1107-2041G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000355.4(TCN2):​c.1107-2041G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 152,186 control chromosomes in the GnomAD database, including 902 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (902 hom., cov: 33)
• Consequence: TCN2 NM_000355.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.14 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.1107-2041G>A		intron	N/A	NP_000346.2
	TCN2	NM_001184726.2		c.1026-2041G>A		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.1107-2041G>A		intron	N/A	ENSP00000215838.3	P20062-1
	TCN2	ENST00000407817.3	TSL:1	c.1026-2041G>A		intron	N/A	ENSP00000384914.3	P20062-2
	TCN2	ENST00000947107.1		c.1230-2041G>A		intron	N/A	ENSP00000617166.1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15685 AN: 152068 Hom.: 897 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0819

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0743

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0955

Gnomad OTH AF: 0.0999

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

GnomAD4 genome AF: 0.103 AC: 15706 AN: 152186 Hom.: 902 Cov.: 33 AF XY: 0.106 AC XY: 7853 AN XY: 74404

African (AFR) AF: 0.110 AC: 4562 AN: 41514

American (AMR) AF: 0.145 AC: 2219 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0819 AC: 284 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5188

South Asian (SAS) AF: 0.0746 AC: 359 AN: 4814

European-Finnish (FIN) AF: 0.142 AC: 1503 AN: 10598

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0956 AC: 6499 AN: 68006

Other (OTH) AF: 0.0993 AC: 210 AN: 2114

Alfa AF: 0.0938 Hom.: 504

Bravo AF: 0.101

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.53
DANN	Benign	0.52
PhyloP100		0.011
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: rs4820887; hg19: chr22-31016914;