chr22-30626965-C-T

Variant names:

• chr22-30626965-C-T
• rs10418
• NM_000355.4:c.*444C>T

Variant summary

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

The NM_000355.4(TCN2):​c.*444C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 268,302 control chromosomes in the GnomAD database, including 8,787 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 0.26 (5447 hom., cov: 34)
  • Exomes 𝑓: 0.23 (3340 hom.)
• Consequence: TCN2 NM_000355.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.308
• Publications: 22 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.*444C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.*444C>T		3_prime_UTR_variant	Exon 9 of 9		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.*444C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39859 AN: 152116 Hom.: 5443 Cov.: 34

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.234 AC: 27215 AN: 116066 Hom.: 3340 Cov.: 0 AF XY: 0.230 AC XY: 14122 AN XY: 61280

African (AFR) AF: 0.340 AC: 1486 AN: 4368

American (AMR) AF: 0.214 AC: 1325 AN: 6200

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 590 AN: 2882

East Asian (EAS) AF: 0.191 AC: 1201 AN: 6278

South Asian (SAS) AF: 0.211 AC: 3777 AN: 17864

European-Finnish (FIN) AF: 0.279 AC: 1349 AN: 4838

Middle Eastern (MID) AF: 0.285 AC: 119 AN: 418

European-Non Finnish (NFE) AF: 0.236 AC: 15899 AN: 67258

Other (OTH) AF: 0.246 AC: 1469 AN: 5960

GnomAD4 genome AF: 0.262 AC: 39879 AN: 152236 Hom.: 5447 Cov.: 34 AF XY: 0.261 AC XY: 19405 AN XY: 74426

African (AFR) AF: 0.348 AC: 14443 AN: 41542

American (AMR) AF: 0.215 AC: 3287 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 713 AN: 3470

East Asian (EAS) AF: 0.192 AC: 991 AN: 5174

South Asian (SAS) AF: 0.211 AC: 1017 AN: 4828

European-Finnish (FIN) AF: 0.280 AC: 2967 AN: 10602

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15695 AN: 68004

Other (OTH) AF: 0.237 AC: 501 AN: 2114

Alfa AF: 0.228 Hom.: 5906

Bravo AF: 0.259

Asia WGS AF: 0.242 AC: 843 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Transcobalamin II deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.3
DANN	Benign	0.44
PhyloP100		-0.31
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: rs10418; hg19: chr22-31022952;