rs2072195

Variant names:

• chr22-30626746-A-T
• rs2072195
• NM_000355.4:c.*225A>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.*225A>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 0.0692 in 613,678 control chromosomes in the GnomAD database, including 4,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2563 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2182 hom.)
• Consequence: TCN2 NM_000355.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.917
• 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=-0.84).
• BP6: Variant 22-30626746-A-T is Benign according to our data. Variant chr22-30626746-A-T is described in ClinVar as Benign. ClinVar VariationId is 341221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 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.*225A>T		3_prime_UTR	Exon 9 of 9	NP_000346.2
	TCN2	NM_001184726.2		c.*225A>T		3_prime_UTR	Exon 9 of 9	NP_001171655.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCN2	ENST00000215838.8	TSL:1 MANE Select	c.*225A>T		3_prime_UTR	Exon 9 of 9	ENSP00000215838.3
	TCN2	ENST00000407817.3	TSL:1	c.*225A>T		3_prime_UTR	Exon 9 of 9	ENSP00000384914.3
	TCN2	ENST00000947107.1		c.*225A>T		3_prime_UTR	Exon 10 of 10	ENSP00000617166.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18474 AN: 152162 Hom.: 2553 Cov.: 33

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.0220

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0932

GnomAD4 exome AF: 0.0519 AC: 23942 AN: 461396 Hom.: 2182 Cov.: 4 AF XY: 0.0489 AC XY: 11877 AN XY: 243008

African (AFR) AF: 0.313 AC: 4152 AN: 13276

American (AMR) AF: 0.173 AC: 3962 AN: 22850

Ashkenazi Jewish (ASJ) AF: 0.0252 AC: 358 AN: 14212

East Asian (EAS) AF: 0.251 AC: 7693 AN: 30680

South Asian (SAS) AF: 0.0359 AC: 1706 AN: 47488

European-Finnish (FIN) AF: 0.0197 AC: 576 AN: 29250

Middle Eastern (MID) AF: 0.0409 AC: 81 AN: 1980

European-Non Finnish (NFE) AF: 0.0139 AC: 3817 AN: 275184

Other (OTH) AF: 0.0603 AC: 1597 AN: 26476

GnomAD4 genome AF: 0.122 AC: 18515 AN: 152282 Hom.: 2563 Cov.: 33 AF XY: 0.121 AC XY: 9018 AN XY: 74458

African (AFR) AF: 0.324 AC: 13438 AN: 41516

American (AMR) AF: 0.137 AC: 2095 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 97 AN: 3468

East Asian (EAS) AF: 0.249 AC: 1289 AN: 5182

South Asian (SAS) AF: 0.0354 AC: 171 AN: 4828

European-Finnish (FIN) AF: 0.0220 AC: 234 AN: 10630

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0141 AC: 961 AN: 68030

Other (OTH) AF: 0.0926 AC: 196 AN: 2116

Alfa AF: 0.0688 Hom.: 171

Bravo AF: 0.142

Asia WGS AF: 0.137 AC: 479 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	-0.84
CADD	Benign	0.69
DANN	Benign	0.40
PhyloP100		-0.92
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: rs2072195; hg19: chr22-31022733;