NM_000355.4:c.754-31T>C

Variant names:

• chr22-30615570-T-C
• rs2267163
• NM_000355.4:c.754-31T>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.754-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,238 control chromosomes in the GnomAD database, including 258,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.62 (29845 hom., cov: 32)
  • Exomes 𝑓: 0.56 (228923 hom.)
• Consequence: TCN2 NM_000355.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.272
• Publications: 22 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 22-30615570-T-C is Benign according to our data. Variant chr22-30615570-T-C is described in ClinVar as Benign. ClinVar VariationId is 1236541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	NM_000355.4	MANE Select	c.754-31T>C		intron	N/A	NP_000346.2
	TCN2	NM_001184726.2		c.673-31T>C		intron	N/A	NP_001171655.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	ENST00000215838.8	TSL:1 MANE Select	c.754-31T>C		intron	N/A	ENSP00000215838.3
	TCN2	ENST00000407817.3	TSL:1	c.673-31T>C		intron	N/A	ENSP00000384914.3
	TCN2	ENST00000698271.1		c.784-31T>C		intron	N/A	ENSP00000513642.1

Frequencies

GnomAD3 genomes AF: 0.619 AC: 94080 AN: 151878 Hom.: 29815 Cov.: 32

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.604

GnomAD2 exomes AF: 0.569 AC: 142218 AN: 249820 AF XY: 0.559

Gnomad AFR exome AF: 0.763

Gnomad AMR exome AF: 0.667

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: 811838 AN: 1461242 Hom.: 228923 Cov.: 48 AF XY: 0.551 AC XY: 400763 AN XY: 726854

African (AFR) AF: 0.779 AC: 26078 AN: 33464

American (AMR) AF: 0.663 AC: 29634 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 15312 AN: 26124

East Asian (EAS) AF: 0.445 AC: 17660 AN: 39690

South Asian (SAS) AF: 0.419 AC: 36103 AN: 86240

European-Finnish (FIN) AF: 0.635 AC: 33851 AN: 53312

Middle Eastern (MID) AF: 0.547 AC: 3153 AN: 5768

European-Non Finnish (NFE) AF: 0.554 AC: 615843 AN: 1111614

Other (OTH) AF: 0.567 AC: 34204 AN: 60364

GnomAD4 genome AF: 0.619 AC: 94161 AN: 151996 Hom.: 29845 Cov.: 32 AF XY: 0.618 AC XY: 45880 AN XY: 74266

African (AFR) AF: 0.758 AC: 31467 AN: 41490

American (AMR) AF: 0.647 AC: 9872 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2023 AN: 3468

East Asian (EAS) AF: 0.441 AC: 2275 AN: 5160

South Asian (SAS) AF: 0.407 AC: 1964 AN: 4820

European-Finnish (FIN) AF: 0.633 AC: 6681 AN: 10554

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

European-Non Finnish (NFE) AF: 0.559 AC: 37948 AN: 67944

Other (OTH) AF: 0.598 AC: 1255 AN: 2100

Alfa AF: 0.585 Hom.: 38578

Bravo AF: 0.628

Asia WGS AF: 0.467 AC: 1627 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Transcobalamin II deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.70
PhyloP100		-0.27
BranchPoint Hunter		0.0
Mutation Taster		=100/0	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: rs2267163; hg19: chr22-31011557; COSMIC: COSV53191518; COSMIC: COSV53191518;