NM_000355.4:c.1107-1557T>C

Variant names:

• chr22-30621411-T-C
• rs2267164
• NM_000355.4:c.1107-1557T>C

Variant summary

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

The NM_000355.4(TCN2):​c.1107-1557T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.671 in 151,948 control chromosomes in the GnomAD database, including 35,485 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 0.67 (35485 hom., cov: 32)
• Consequence: TCN2 NM_000355.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.364
• Publications: 1 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.864 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.1107-1557T>C		intron	N/A	NP_000346.2
	TCN2	NM_001184726.2		c.1026-1557T>C		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.1107-1557T>C		intron	N/A	ENSP00000215838.3
	TCN2	ENST00000407817.3	TSL:1	c.1026-1557T>C		intron	N/A	ENSP00000384914.3
	TCN2	ENST00000698271.1		c.1137-1557T>C		intron	N/A	ENSP00000513642.1

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101829 AN: 151830 Hom.: 35428 Cov.: 32

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.655

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

GnomAD4 genome AF: 0.671 AC: 101938 AN: 151948 Hom.: 35485 Cov.: 32 AF XY: 0.668 AC XY: 49618 AN XY: 74252

African (AFR) AF: 0.871 AC: 36160 AN: 41506

American (AMR) AF: 0.681 AC: 10391 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2098 AN: 3470

East Asian (EAS) AF: 0.448 AC: 2316 AN: 5168

South Asian (SAS) AF: 0.453 AC: 2182 AN: 4822

European-Finnish (FIN) AF: 0.646 AC: 6783 AN: 10496

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.588 AC: 39902 AN: 67914

Other (OTH) AF: 0.648 AC: 1368 AN: 2110

Alfa AF: 0.655 Hom.: 4674

Bravo AF: 0.683

Asia WGS AF: 0.494 AC: 1721 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.51
PhyloP100		-0.36
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: rs2267164; hg19: chr22-31017398;