rs740234

Variant names:

• chr22-30612758-A-G
• rs740234
• NM_000355.4:c.258-115A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-30612758-A-G
• chr22-30612758-A-T

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.258-115A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,332,756 control chromosomes in the GnomAD database, including 23,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2081 hom., cov: 32)
  • Exomes 𝑓: 0.18 (21326 hom.)
• Consequence: TCN2 NM_000355.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.858
• Publications: 11 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 (BayesDel_noAF=-0.83).
• BP6: Variant 22-30612758-A-G is Benign according to our data. Variant chr22-30612758-A-G is described in ClinVar as [Benign]. Clinvar id is 1269240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.258-115A>G		intron_variant	Intron 2 of 8	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.258-115A>G		intron_variant	Intron 2 of 8		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.258-115A>G		intron_variant	Intron 2 of 8	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24128 AN: 152028 Hom.: 2079 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0844

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.171

GnomAD4 exome AF: 0.181 AC: 214206 AN: 1180610 Hom.: 21326 AF XY: 0.179 AC XY: 105511 AN XY: 590104

African (AFR) AF: 0.110 AC: 3072 AN: 27806

American (AMR) AF: 0.110 AC: 4011 AN: 36334

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6007 AN: 23424

East Asian (EAS) AF: 0.000337 AC: 12 AN: 35630

South Asian (SAS) AF: 0.0919 AC: 6917 AN: 75294

European-Finnish (FIN) AF: 0.184 AC: 7170 AN: 39030

Middle Eastern (MID) AF: 0.136 AC: 497 AN: 3644

European-Non Finnish (NFE) AF: 0.200 AC: 177504 AN: 888784

Other (OTH) AF: 0.178 AC: 9016 AN: 50664

GnomAD4 genome AF: 0.159 AC: 24137 AN: 152146 Hom.: 2081 Cov.: 32 AF XY: 0.157 AC XY: 11642 AN XY: 74368

African (AFR) AF: 0.112 AC: 4649 AN: 41528

American (AMR) AF: 0.148 AC: 2259 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 870 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0843 AC: 407 AN: 4828

European-Finnish (FIN) AF: 0.176 AC: 1864 AN: 10582

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

European-Non Finnish (NFE) AF: 0.198 AC: 13463 AN: 67988

Other (OTH) AF: 0.168 AC: 355 AN: 2108

Alfa AF: 0.185 Hom.: 8086

Bravo AF: 0.155

Asia WGS AF: 0.0370 AC: 130 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.8
DANN	Benign	0.51
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs740234; hg19: chr22-31008745;