chr22-30615293-A-G

Variant names:

• chr22-30615293-A-G
• rs7290898
• NM_000355.4:c.581-8A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000355.4(TCN2):​c.581-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,613,772 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: TCN2 NM_000355.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001367
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 22-30615293-A-G is Benign according to our data. Variant chr22-30615293-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529779.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00127 (193/151928) while in subpopulation AFR AF = 0.00418 (173/41430). AF 95% confidence interval is 0.00367. There are 1 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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>G		splice_region intron	N/A	NP_000346.2
	TCN2	NM_001184726.2		c.500-8A>G		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>G		splice_region intron	N/A	ENSP00000215838.3
	TCN2	ENST00000407817.3	TSL:1	c.500-8A>G		splice_region intron	N/A	ENSP00000384914.3
	TCN2	ENST00000698271.1		c.603A>G	p.Pro201Pro	synonymous	Exon 5 of 9	ENSP00000513642.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 151810 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00414

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000287 AC: 72 AN: 251190 AF XY: 0.000214

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000142 AC: 208 AN: 1461844 Hom.: 0 Cov.: 32 AF XY: 0.000127 AC XY: 92 AN XY: 727220

African (AFR) AF: 0.00517 AC: 173 AN: 33478

American (AMR) AF: 0.000313 AC: 14 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.000265 AC: 16 AN: 60396

GnomAD4 genome AF: 0.00127 AC: 193 AN: 151928 Hom.: 1 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74226

African (AFR) AF: 0.00418 AC: 173 AN: 41430

American (AMR) AF: 0.00111 AC: 17 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67956

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00 Hom.: 392

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Transcobalamin II deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.33
DANN	Benign	0.56
PhyloP100		-1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.090		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;