rs9606756

Variant names:

• chr22-30610873-A-G
• rs9606756
• NM_000355.4:c.67A>G

Variant summary

Our verdict is Benign. The variant received -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. 14/23 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I23L) has been classified as Uncertain significance.

• 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:4
• Conservation: PhyloP100: 0.0800
• Publications: 69 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: PanelApp Australia, ClinGen, Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PP3: Splicing predictors support a deleterious 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000355.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	NM_000355.4	MANE Select	c.67A>G	p.Ile23Val	missense splice_region	Exon 2 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.67A>G	p.Ile23Val	missense splice_region	Exon 2 of 9	NP_001171655.1	P20062-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	ENST00000215838.8	TSL:1 MANE Select	c.67A>G	p.Ile23Val	missense splice_region	Exon 2 of 9	ENSP00000215838.3	P20062-1
	TCN2	ENST00000407817.3	TSL:1	c.67A>G	p.Ile23Val	missense splice_region	Exon 2 of 9	ENSP00000384914.3	P20062-2
	TCN2	ENST00000947107.1		c.67A>G	p.Ile23Val	missense splice_region	Exon 2 of 10	ENSP00000617166.1

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

GnomAD2 exomes AF: 0.118 AC: 29699 AN: 251470 AF XY: 0.116

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 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

African (AFR) AF: 0.162 AC: 5418 AN: 33476

American (AMR) AF: 0.163 AC: 7298 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0869 AC: 2270 AN: 26136

East Asian (EAS) AF: 0.0205 AC: 813 AN: 39700

South Asian (SAS) AF: 0.0982 AC: 8470 AN: 86254

European-Finnish (FIN) AF: 0.152 AC: 8132 AN: 53420

Middle Eastern (MID) AF: 0.117 AC: 675 AN: 5766

European-Non Finnish (NFE) AF: 0.123 AC: 136244 AN: 1111898

Other (OTH) AF: 0.116 AC: 7009 AN: 60394

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

African (AFR) AF: 0.163 AC: 6753 AN: 41506

American (AMR) AF: 0.164 AC: 2505 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3470

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5178

South Asian (SAS) AF: 0.0934 AC: 450 AN: 4816

European-Finnish (FIN) AF: 0.156 AC: 1657 AN: 10592

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8210 AN: 68004

Other (OTH) AF: 0.132 AC: 279 AN: 2114

Alfa AF: 0.118 Hom.: 5086

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Transcobalamin II deficiency (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.080
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.047
Sift	Benign	0.11	T
Sift4G	Benign	0.088	T
Polyphen		0.0020	B
Vest4		0.088
MPC		0.0099
ClinPred		0.0041	T
GERP RS		1.3
Varity_R		0.044
gMVP		0.071
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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