rs76802001

chr22-30617412-G-Achr22-30617412-G-T

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.1023G>A(p.Pro341=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,614,028 control chromosomes in the GnomAD database, including 957 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (65 hom., cov: 31)
  • Exomes 𝑓: 0.032 (892 hom.)
• Consequence: TCN2 NM_000355.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.94

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=-0.87).
• BP6: Variant 22-30617412-G-A is Benign according to our data. Variant chr22-30617412-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 341210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.94 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0246 (3744/152158) while in subpopulation AMR AF= 0.039 (596/15268). AF 95% confidence interval is 0.0364. There are 65 homozygotes in gnomad4. There are 1771 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 65 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCN2	NM_000355.4	c.1023G>A	p.Pro341=	synonymous_variant	7/9	ENST00000215838.8
TCN2	NM_001184726.2	c.942G>A	p.Pro314=	synonymous_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000215838.8	c.1023G>A	p.Pro341=	synonymous_variant	7/9	1	NM_000355.4	P2

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3743 AN: 152040 Hom.: 65 Cov.: 31

Gnomad AFR AF: 0.00708

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0390

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0358

Gnomad OTH AF: 0.0297

GnomAD3 exomes AF: 0.0253 AC: 6366 AN: 251470 Hom.: 123 AF XY: 0.0255 AC XY: 3466 AN XY: 135914

Gnomad AFR exome AF: 0.00701

Gnomad AMR exome AF: 0.0296

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00990

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0362

Gnomad OTH exome AF: 0.0336

GnomAD4 exome AF: 0.0319 AC: 46561 AN: 1461870 Hom.: 892 Cov.: 32 AF XY: 0.0313 AC XY: 22735 AN XY: 727240

Gnomad4 AFR exome AF: 0.00606

Gnomad4 AMR exome AF: 0.0315

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00982

Gnomad4 FIN exome AF: 0.0222

Gnomad4 NFE exome AF: 0.0364

Gnomad4 OTH exome AF: 0.0314

GnomAD4 genome AF: 0.0246 AC: 3744 AN: 152158 Hom.: 65 Cov.: 31 AF XY: 0.0238 AC XY: 1771 AN XY: 74396

Gnomad4 AFR AF: 0.00706

Gnomad4 AMR AF: 0.0390

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.00892

Gnomad4 FIN AF: 0.0218

Gnomad4 NFE AF: 0.0358

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.0265 Hom.: 24

Bravo AF: 0.0256

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0374

EpiControl AF: 0.0376

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.23
Dann	Benign	0.54

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: rs76802001; hg19: chr22-31013399;