22-30615293-A-C

Variant names:

• chr22-30615293-A-C
• rs7290898
• NM_000355.4:c.581-8A>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.581-8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,613,694 control chromosomes in the GnomAD database, including 6,231 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2162 hom., cov: 32)
  • Exomes 𝑓: 0.035 (4069 hom.)
• Consequence: TCN2 NM_000355.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001423
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.71
• 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=-0.95).
• BP6: Variant 22-30615293-A-C is Benign according to our data. Variant chr22-30615293-A-C is described in ClinVar as Benign. ClinVar VariationId is 341199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 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.581-8A>C		splice_region intron	N/A	NP_000346.2
	TCN2	NM_001184726.2		c.500-8A>C		splice_region 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.581-8A>C		splice_region intron	N/A	ENSP00000215838.3
	TCN2	ENST00000407817.3	TSL:1	c.500-8A>C		splice_region intron	N/A	ENSP00000384914.3
	TCN2	ENST00000698271.1		c.603A>C	p.Pro201Pro	synonymous	Exon 5 of 9	ENSP00000513642.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17109 AN: 151780 Hom.: 2154 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.0345

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0857

GnomAD2 exomes AF: 0.0793 AC: 19918 AN: 251190 AF XY: 0.0666

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.0235

Gnomad EAS exome AF: 0.225

Gnomad FIN exome AF: 0.0241

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0440

GnomAD4 exome AF: 0.0349 AC: 51048 AN: 1461796 Hom.: 4069 Cov.: 32 AF XY: 0.0333 AC XY: 24213 AN XY: 727200

African (AFR) AF: 0.310 AC: 10368 AN: 33462

American (AMR) AF: 0.193 AC: 8613 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 684 AN: 26136

East Asian (EAS) AF: 0.237 AC: 9413 AN: 39696

South Asian (SAS) AF: 0.0356 AC: 3069 AN: 86258

European-Finnish (FIN) AF: 0.0211 AC: 1125 AN: 53392

Middle Eastern (MID) AF: 0.0400 AC: 231 AN: 5768

European-Non Finnish (NFE) AF: 0.0130 AC: 14455 AN: 1111974

Other (OTH) AF: 0.0512 AC: 3090 AN: 60394

GnomAD4 genome AF: 0.113 AC: 17152 AN: 151898 Hom.: 2162 Cov.: 32 AF XY: 0.112 AC XY: 8345 AN XY: 74212

African (AFR) AF: 0.298 AC: 12322 AN: 41402

American (AMR) AF: 0.131 AC: 1991 AN: 15254

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

East Asian (EAS) AF: 0.230 AC: 1184 AN: 5142

South Asian (SAS) AF: 0.0343 AC: 165 AN: 4804

European-Finnish (FIN) AF: 0.0222 AC: 234 AN: 10556

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 948 AN: 67956

Other (OTH) AF: 0.0853 AC: 180 AN: 2110

Alfa AF: 0.0555 Hom.: 392

Bravo AF: 0.132

EpiCase AF: 0.0177

EpiControl AF: 0.0170

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.14
DANN	Benign	0.45
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.010
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: rs7290898; hg19: chr22-31011280; COSMIC: COSV53191563; COSMIC: COSV53191563;