rs9606756

chr22-30610873-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_000355.4(TCN2):c.67A>G(p.Ile23Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,613,936 control chromosomes in the GnomAD database, including 12,749 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1488 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11261 hom.)
• Consequence: TCN2 NM_000355.4 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0800

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 -14 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 22-30610873-A-G is Benign according to our data. Variant chr22-30610873-A-G is described in ClinVar as [Benign]. Clinvar id is 341188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCN2	NM_000355.4	c.67A>G	p.Ile23Val	missense_variant, splice_region_variant	2/9	ENST00000215838.8
TCN2	NM_001184726.2	c.67A>G	p.Ile23Val	missense_variant, splice_region_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000215838.8	c.67A>G	p.Ile23Val	missense_variant, splice_region_variant	2/9	1	NM_000355.4	P2

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20321 AN: 152050 Hom.: 1478 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.118 AC: 29699 AN: 251470 Hom.: 2023 AF XY: 0.116 AC XY: 15751 AN XY: 135908

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.0880

Gnomad EAS exome AF: 0.0210

Gnomad SAS exome AF: 0.0976

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.121 AC: 176329 AN: 1461768 Hom.: 11261 Cov.: 32 AF XY: 0.120 AC XY: 87165 AN XY: 727192

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.0869

Gnomad4 EAS exome AF: 0.0205

Gnomad4 SAS exome AF: 0.0982

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.134 AC: 20356 AN: 152168 Hom.: 1488 Cov.: 32 AF XY: 0.135 AC XY: 10050 AN XY: 74390

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.0836

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.0934

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.132

Alfa AF: 0.116 Hom.: 2674

Bravo AF: 0.133

TwinsUK AF: 0.118 AC: 439

ALSPAC AF: 0.120 AC: 464

ESP6500AA AF: 0.154 AC: 678

ESP6500EA AF: 0.116 AC: 1001

ExAC AF: 0.117 AC: 14139

Asia WGS AF: 0.0840 AC: 290 AN: 3478

EpiCase AF: 0.116

EpiControl AF: 0.115

ClinVar

Significance: 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	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2018

This variant is associated with the following publications: (PMID: 12107818, 21975197, 22102315, 21214274) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	23
Dann	Benign	0.92
DEOGEN2	Benign	0.027	T;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.40	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.010	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.088	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.088
MPC		0.0099
ClinPred		0.0041	T
GERP RS		1.3
Varity_R		0.044
gMVP		0.071

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.93		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9606756; hg19: chr22-31006860; COSMIC: COSV53191690; COSMIC: COSV53191690;