rs45624233

Variant names:

• chr22-30615724-C-T
• rs45624233
• NM_000355.4:c.877C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-30615724-C-T
• chr22-30615724-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000355.4(TCN2):​c.877C>T​(p.Leu293Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,614,200 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L293L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (26 hom.)
• Consequence: TCN2 NM_000355.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.49
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 22-30615724-C-T is Benign according to our data. Variant chr22-30615724-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 341204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00334 (509/152306) while in subpopulation NFE AF = 0.00588 (400/68026). AF 95% confidence interval is 0.0054. There are 0 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 26 AR gene

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.877C>T	p.Leu293Leu	synonymous	Exon 6 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.796C>T	p.Leu266Leu	synonymous	Exon 6 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.877C>T	p.Leu293Leu	synonymous	Exon 6 of 9	ENSP00000215838.3	P20062-1
	TCN2	ENST00000407817.3	TSL:1	c.796C>T	p.Leu266Leu	synonymous	Exon 6 of 9	ENSP00000384914.3	P20062-2
	TCN2	ENST00000947107.1		c.877C>T	p.Leu293Leu	synonymous	Exon 6 of 10	ENSP00000617166.1

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 509 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00362 AC: 911 AN: 251464 AF XY: 0.00330

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00573

Gnomad NFE exome AF: 0.00637

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00543 AC: 7935 AN: 1461894 Hom.: 26 Cov.: 35 AF XY: 0.00531 AC XY: 3864 AN XY: 727248

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.000559 AC: 25 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.00627 AC: 335 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00656 AC: 7300 AN: 1112012

Other (OTH) AF: 0.00366 AC: 221 AN: 60396

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00313 AC XY: 233 AN XY: 74482

African (AFR) AF: 0.00106 AC: 44 AN: 41572

American (AMR) AF: 0.000654 AC: 10 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00588 AC: 400 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00480 Hom.: 5

Bravo AF: 0.00309

EpiCase AF: 0.00474

EpiControl AF: 0.00528

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Transcobalamin II deficiency (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.6
DANN	Benign	0.78
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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: rs45624233; hg19: chr22-31011711;