NM_000355.4:c.1107-138C>G

Variant names:

• chr22-30622830-C-G
• rs2301957
• NM_000355.4:c.1107-138C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000355.4(TCN2):​c.1107-138C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 676,478 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TCN2 NM_000355.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.92
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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.1107-138C>G		intron	N/A	NP_000346.2
	TCN2	NM_001184726.2		c.1026-138C>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.1107-138C>G		intron	N/A	ENSP00000215838.3
	TCN2	ENST00000407817.3	TSL:1	c.1026-138C>G		intron	N/A	ENSP00000384914.3
	TCN2	ENST00000698271.1		c.1137-138C>G		intron	N/A	ENSP00000513642.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000148 AC: 1 AN: 676478 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 359284

African (AFR) AF: 0.00 AC: 0 AN: 18218

American (AMR) AF: 0.00 AC: 0 AN: 35460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20624

East Asian (EAS) AF: 0.00 AC: 0 AN: 33004

South Asian (SAS) AF: 0.00 AC: 0 AN: 65738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4252

European-Non Finnish (NFE) AF: 0.00000238 AC: 1 AN: 420766

Other (OTH) AF: 0.00 AC: 0 AN: 34474

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 1409

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.14
DANN	Benign	0.41
PhyloP100		-2.9

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: rs2301957; hg19: chr22-31018817;