22-30615623-G-C

Variant names:

• chr22-30615623-G-C
• rs1801198
• NM_000355.4:c.776G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000355.4(TCN2):​c.776G>C​(p.Arg259Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,732 control chromosomes in the GnomAD database, including 258,781 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.62 (29857 hom., cov: 32)
  • Exomes 𝑓: 0.56 (228924 hom.)
• Consequence: TCN2 NM_000355.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.373
• Publications: 227 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4999782E-6).
• BP6: Variant 22-30615623-G-C is Benign according to our data. Variant chr22-30615623-G-C is described in ClinVar as Benign. ClinVar VariationId is 97.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.776G>C	p.Arg259Pro	missense_variant	Exon 6 of 9	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.695G>C	p.Arg232Pro	missense_variant	Exon 6 of 9		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.776G>C	p.Arg259Pro	missense_variant	Exon 6 of 9	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94100 AN: 151870 Hom.: 29826 Cov.: 32

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.602

GnomAD2 exomes AF: 0.569 AC: 142938 AN: 251026 AF XY: 0.559

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.666

Gnomad ASJ exome AF: 0.591

Gnomad EAS exome AF: 0.428

Gnomad FIN exome AF: 0.635

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.578

GnomAD4 exome AF: 0.556 AC: 812000 AN: 1461744 Hom.: 228924 Cov.: 68 AF XY: 0.551 AC XY: 400881 AN XY: 727162

African (AFR) AF: 0.780 AC: 26098 AN: 33480

American (AMR) AF: 0.663 AC: 29649 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 15312 AN: 26134

East Asian (EAS) AF: 0.445 AC: 17669 AN: 39698

South Asian (SAS) AF: 0.419 AC: 36109 AN: 86254

European-Finnish (FIN) AF: 0.635 AC: 33876 AN: 53368

Middle Eastern (MID) AF: 0.545 AC: 3141 AN: 5768

European-Non Finnish (NFE) AF: 0.554 AC: 615949 AN: 1111934

Other (OTH) AF: 0.566 AC: 34197 AN: 60390

GnomAD4 genome AF: 0.620 AC: 94182 AN: 151988 Hom.: 29857 Cov.: 32 AF XY: 0.618 AC XY: 45900 AN XY: 74262

African (AFR) AF: 0.759 AC: 31493 AN: 41486

American (AMR) AF: 0.646 AC: 9856 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2021 AN: 3464

East Asian (EAS) AF: 0.441 AC: 2269 AN: 5150

South Asian (SAS) AF: 0.408 AC: 1963 AN: 4814

European-Finnish (FIN) AF: 0.634 AC: 6690 AN: 10554

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.559 AC: 37960 AN: 67960

Other (OTH) AF: 0.595 AC: 1254 AN: 2106

Alfa AF: 0.535 Hom.: 5859

Bravo AF: 0.628

TwinsUK AF: 0.555 AC: 2057

ALSPAC AF: 0.551 AC: 2125

ESP6500AA AF: 0.765 AC: 3372

ESP6500EA AF: 0.566 AC: 4865

ExAC AF: 0.567 AC: 68821

Asia WGS AF: 0.467 AC: 1627 AN: 3478

EpiCase AF: 0.566

EpiControl AF: 0.574

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Transcobalamin II deficiency Benign:5

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 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.

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2 Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.

Jul 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12091374, 21975197, 14680986, 19353223, 12107818, 19936946, 22794911, 23099805)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

TCN2 POLYMORPHISM Benign:1

Jun 01, 2007

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.5
DANN	Benign	0.25
DEOGEN2	Benign	0.019	T;T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.29	T;T;T;T
MetaRNN	Benign	0.0000015	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.5	N;.;.;.
PhyloP100		0.37
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.3	N;.;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	0.59	T;T;T;T
Vest4		0.050
ClinPred		0.0088	T
GERP RS		4.1
Varity_R		0.42
gMVP		0.42
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1801198; hg19: chr22-31011610; COSMIC: COSV53190706; COSMIC: COSV53190706;