22-30627204-A-G

Variant names:

• chr22-30627204-A-G
• rs1544468
• NM_000355.4:c.*683A>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.*683A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 160,566 control chromosomes in the GnomAD database, including 16,816 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 0.45 (15936 hom., cov: 34)
  • Exomes 𝑓: 0.43 (880 hom.)
• Consequence: TCN2 NM_000355.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 4 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.502 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.*683A>G		3_prime_UTR	Exon 9 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.*683A>G		3_prime_UTR	Exon 9 of 9	NP_001171655.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	ENST00000215838.8	TSL:1 MANE Select	c.*683A>G		3_prime_UTR	Exon 9 of 9	ENSP00000215838.3
	TCN2	ENST00000698269.1		n.*1533A>G		non_coding_transcript_exon	Exon 8 of 8	ENSP00000513640.1
	TCN2	ENST00000698271.1		c.*683A>G		3_prime_UTR	Exon 9 of 9	ENSP00000513642.1

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68103 AN: 151972 Hom.: 15923 Cov.: 34

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.494

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.460

GnomAD4 exome AF: 0.426 AC: 3609 AN: 8476 Hom.: 880 Cov.: 0 AF XY: 0.415 AC XY: 1828 AN XY: 4408

African (AFR) AF: 0.208 AC: 25 AN: 120

American (AMR) AF: 0.444 AC: 983 AN: 2212

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 33 AN: 54

East Asian (EAS) AF: 0.119 AC: 51 AN: 428

South Asian (SAS) AF: 0.294 AC: 262 AN: 890

European-Finnish (FIN) AF: 0.500 AC: 32 AN: 64

Middle Eastern (MID) AF: 0.333 AC: 2 AN: 6

European-Non Finnish (NFE) AF: 0.472 AC: 2078 AN: 4398

Other (OTH) AF: 0.470 AC: 143 AN: 304

GnomAD4 genome AF: 0.448 AC: 68134 AN: 152090 Hom.: 15936 Cov.: 34 AF XY: 0.450 AC XY: 33439 AN XY: 74344

African (AFR) AF: 0.338 AC: 14025 AN: 41480

American (AMR) AF: 0.486 AC: 7437 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1806 AN: 3470

East Asian (EAS) AF: 0.197 AC: 1017 AN: 5162

South Asian (SAS) AF: 0.339 AC: 1636 AN: 4824

European-Finnish (FIN) AF: 0.588 AC: 6223 AN: 10580

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.507 AC: 34453 AN: 67964

Other (OTH) AF: 0.455 AC: 961 AN: 2114

Alfa AF: 0.483 Hom.: 4669

Bravo AF: 0.434

Asia WGS AF: 0.306 AC: 1066 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.65
PhyloP100		-1.1
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: rs1544468; hg19: chr22-31023191;