rs79999752

chr22-30615687-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000355.4(TCN2):c.840T>C(p.Asp280=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,614,230 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (15 hom.)
• Consequence: TCN2 NM_000355.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.26

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 22-30615687-T-C is Benign according to our data. Variant chr22-30615687-T-C is described in ClinVar as [Benign]. Clinvar id is 341203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-30615687-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00737 (1123/152340) while in subpopulation AFR AF= 0.0248 (1032/41564). AF 95% confidence interval is 0.0236. There are 15 homozygotes in gnomad4. There are 520 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCN2	NM_000355.4	c.840T>C	p.Asp280=	synonymous_variant	6/9	ENST00000215838.8
TCN2	NM_001184726.2	c.759T>C	p.Asp253=	synonymous_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000215838.8	c.840T>C	p.Asp280=	synonymous_variant	6/9	1	NM_000355.4	P2

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1123 AN: 152222 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00227 AC: 572 AN: 251446 Hom.: 9 AF XY: 0.00168 AC XY: 228 AN XY: 135896

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.000976 AC: 1427 AN: 1461890 Hom.: 15 Cov.: 35 AF XY: 0.000846 AC XY: 615 AN XY: 727246

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000234

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00737 AC: 1123 AN: 152340 Hom.: 15 Cov.: 33 AF XY: 0.00698 AC XY: 520 AN XY: 74492

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00376 Hom.: 3

Bravo AF: 0.00864

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Transcobalamin II deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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	-0.93
Cadd	Benign	0.020
Dann	Benign	0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs79999752; hg19: chr22-31011674;