chr22-30613131-T-A

Variant names:

• chr22-30613131-T-A
• rs11703570
• NM_000355.4:c.427+89T>A

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.427+89T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,535,186 control chromosomes in the GnomAD database, including 38,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3657 hom., cov: 32)
  • Exomes 𝑓: 0.22 (34929 hom.)
• Consequence: TCN2 NM_000355.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.368
• Publications: 4 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=-0.81).
• BP6: Variant 22-30613131-T-A is Benign according to our data. Variant chr22-30613131-T-A is described in ClinVar as Benign. ClinVar VariationId is 1179882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.427+89T>A		intron_variant	Intron 3 of 8	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.346+170T>A		intron_variant	Intron 3 of 8		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.427+89T>A		intron_variant	Intron 3 of 8	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33276 AN: 151936 Hom.: 3651 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.222

GnomAD4 exome AF: 0.223 AC: 307930 AN: 1383132 Hom.: 34929 AF XY: 0.223 AC XY: 152657 AN XY: 683938

African (AFR) AF: 0.195 AC: 6143 AN: 31464

American (AMR) AF: 0.210 AC: 7615 AN: 36218

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 4980 AN: 25042

East Asian (EAS) AF: 0.197 AC: 7071 AN: 35946

South Asian (SAS) AF: 0.207 AC: 16384 AN: 79106

European-Finnish (FIN) AF: 0.280 AC: 12790 AN: 45752

Middle Eastern (MID) AF: 0.277 AC: 1359 AN: 4900

European-Non Finnish (NFE) AF: 0.224 AC: 238937 AN: 1067266

Other (OTH) AF: 0.220 AC: 12651 AN: 57438

GnomAD4 genome AF: 0.219 AC: 33288 AN: 152054 Hom.: 3657 Cov.: 32 AF XY: 0.219 AC XY: 16271 AN XY: 74334

African (AFR) AF: 0.193 AC: 7993 AN: 41460

American (AMR) AF: 0.207 AC: 3159 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 715 AN: 3468

East Asian (EAS) AF: 0.194 AC: 1001 AN: 5166

South Asian (SAS) AF: 0.210 AC: 1010 AN: 4818

European-Finnish (FIN) AF: 0.281 AC: 2974 AN: 10598

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15708 AN: 67966

Other (OTH) AF: 0.219 AC: 462 AN: 2110

Alfa AF: 0.227 Hom.: 484

Bravo AF: 0.212

Asia WGS AF: 0.240 AC: 834 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.1
DANN	Benign	0.87
PhyloP100		0.37
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: rs11703570; hg19: chr22-31009118;