rs10418

Variant names:

• chr22-30626965-C-T
• rs10418
• NM_000355.4:c.*444C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-30626965-C-T
• chr22-30626965-C-A
• chr22-30626965-C-G

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.*444C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 268,302 control chromosomes in the GnomAD database, including 8,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5447 hom., cov: 34)
  • Exomes 𝑓: 0.23 (3340 hom.)
• Consequence: TCN2 NM_000355.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.308
• 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: PanelApp Australia, ClinGen, Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-30626965-C-T is Benign according to our data. Variant chr22-30626965-C-T is described in ClinVar as Benign. ClinVar VariationId is 341226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 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.*444C>T		3_prime_UTR	Exon 9 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.*444C>T		3_prime_UTR	Exon 9 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.*444C>T		3_prime_UTR	Exon 9 of 9	ENSP00000215838.3	P20062-1
	TCN2	ENST00000407817.3	TSL:1	c.*444C>T		3_prime_UTR	Exon 9 of 9	ENSP00000384914.3	P20062-2
	TCN2	ENST00000947107.1		c.*444C>T		3_prime_UTR	Exon 10 of 10	ENSP00000617166.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39859 AN: 152116 Hom.: 5443 Cov.: 34

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.234 AC: 27215 AN: 116066 Hom.: 3340 Cov.: 0 AF XY: 0.230 AC XY: 14122 AN XY: 61280

African (AFR) AF: 0.340 AC: 1486 AN: 4368

American (AMR) AF: 0.214 AC: 1325 AN: 6200

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 590 AN: 2882

East Asian (EAS) AF: 0.191 AC: 1201 AN: 6278

South Asian (SAS) AF: 0.211 AC: 3777 AN: 17864

European-Finnish (FIN) AF: 0.279 AC: 1349 AN: 4838

Middle Eastern (MID) AF: 0.285 AC: 119 AN: 418

European-Non Finnish (NFE) AF: 0.236 AC: 15899 AN: 67258

Other (OTH) AF: 0.246 AC: 1469 AN: 5960

GnomAD4 genome AF: 0.262 AC: 39879 AN: 152236 Hom.: 5447 Cov.: 34 AF XY: 0.261 AC XY: 19405 AN XY: 74426

African (AFR) AF: 0.348 AC: 14443 AN: 41542

American (AMR) AF: 0.215 AC: 3287 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 713 AN: 3470

East Asian (EAS) AF: 0.192 AC: 991 AN: 5174

South Asian (SAS) AF: 0.211 AC: 1017 AN: 4828

European-Finnish (FIN) AF: 0.280 AC: 2967 AN: 10602

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15695 AN: 68004

Other (OTH) AF: 0.237 AC: 501 AN: 2114

Alfa AF: 0.228 Hom.: 5906

Bravo AF: 0.259

Asia WGS AF: 0.242 AC: 843 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.3
DANN	Benign	0.44
PhyloP100		-0.31
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: rs10418; hg19: chr22-31022952;