22-30622830-C-T

Variant names:

• chr22-30622830-C-T
• rs2301957
• NM_000355.4:c.1107-138C>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.1107-138C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 827,208 control chromosomes in the GnomAD database, including 61,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10073 hom., cov: 31)
  • Exomes 𝑓: 0.38 (51237 hom.)
• Consequence: TCN2 NM_000355.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.92
• Publications: 6 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=-0.93).
• BP6: Variant 22-30622830-C-T is Benign according to our data. Variant chr22-30622830-C-T is described in ClinVar as Benign. ClinVar VariationId is 1267520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.1107-138C>T		intron_variant	Intron 7 of 8	ENST00000215838.8	NP_000346.2
TCN2	NM_001184726.2	c.1026-138C>T		intron_variant	Intron 7 of 8		NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.1107-138C>T		intron_variant	Intron 7 of 8	1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53932 AN: 151860 Hom.: 10071 Cov.: 31

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.365

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.381 AC: 257212 AN: 675230 Hom.: 51237 AF XY: 0.378 AC XY: 135549 AN XY: 358684

African (AFR) AF: 0.255 AC: 4641 AN: 18198

American (AMR) AF: 0.312 AC: 11069 AN: 35426

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 9167 AN: 20600

East Asian (EAS) AF: 0.197 AC: 6489 AN: 32982

South Asian (SAS) AF: 0.270 AC: 17722 AN: 65710

European-Finnish (FIN) AF: 0.455 AC: 19942 AN: 43840

Middle Eastern (MID) AF: 0.364 AC: 1544 AN: 4244

European-Non Finnish (NFE) AF: 0.413 AC: 173381 AN: 419806

Other (OTH) AF: 0.385 AC: 13257 AN: 34424

GnomAD4 genome AF: 0.355 AC: 53938 AN: 151978 Hom.: 10073 Cov.: 31 AF XY: 0.353 AC XY: 26228 AN XY: 74290

African (AFR) AF: 0.251 AC: 10399 AN: 41476

American (AMR) AF: 0.342 AC: 5225 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1551 AN: 3470

East Asian (EAS) AF: 0.193 AC: 1000 AN: 5168

South Asian (SAS) AF: 0.266 AC: 1280 AN: 4812

European-Finnish (FIN) AF: 0.449 AC: 4738 AN: 10560

Middle Eastern (MID) AF: 0.355 AC: 103 AN: 290

European-Non Finnish (NFE) AF: 0.419 AC: 28451 AN: 67920

Other (OTH) AF: 0.366 AC: 774 AN: 2116

Alfa AF: 0.373 Hom.: 1409

Bravo AF: 0.344

Asia WGS AF: 0.264 AC: 920 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.17
DANN	Benign	0.43
PhyloP100		-2.9
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: rs2301957; hg19: chr22-31018817; COSMIC: COSV53191995;