rs4820888

Variant names:

• chr22-30621335-A-G
• rs4820888
• NM_000355.4:c.1107-1633A>G

Variant summary

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

The NM_000355.4(TCN2):​c.1107-1633A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 151,852 control chromosomes in the GnomAD database, including 13,925 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 0.43 (13925 hom., cov: 31)
• Consequence: TCN2 NM_000355.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.58
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.07).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.451 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	NM_000355.4	MANE Select	c.1107-1633A>G		intron	N/A	NP_000346.2
	TCN2	NM_001184726.2		c.1026-1633A>G		intron	N/A	NP_001171655.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	ENST00000215838.8	TSL:1 MANE Select	c.1107-1633A>G		intron	N/A	ENSP00000215838.3
	TCN2	ENST00000407817.3	TSL:1	c.1026-1633A>G		intron	N/A	ENSP00000384914.3
	TCN2	ENST00000698271.1		c.1137-1633A>G		intron	N/A	ENSP00000513642.1

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64502 AN: 151734 Hom.: 13916 Cov.: 31

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.443

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

GnomAD4 genome AF: 0.425 AC: 64542 AN: 151852 Hom.: 13925 Cov.: 31 AF XY: 0.422 AC XY: 31304 AN XY: 74212

African (AFR) AF: 0.410 AC: 16968 AN: 41388

American (AMR) AF: 0.388 AC: 5917 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1637 AN: 3470

East Asian (EAS) AF: 0.198 AC: 1022 AN: 5166

South Asian (SAS) AF: 0.337 AC: 1621 AN: 4812

European-Finnish (FIN) AF: 0.467 AC: 4911 AN: 10506

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30955 AN: 67950

Other (OTH) AF: 0.437 AC: 920 AN: 2104

Alfa AF: 0.444 Hom.: 45018

Bravo AF: 0.418

Asia WGS AF: 0.308 AC: 1073 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.11
DANN	Benign	0.13
PhyloP100		-3.6
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: rs4820888; hg19: chr22-31017322;