22-30607088-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000450638.5(TCN2):c.-420C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00969 in 601,064 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (9 hom., cov: 30)
  • Exomes 𝑓: 0.011 (74 hom.)
• Consequence: TCN2 ENST00000450638.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.808

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]

PES1 (HGNC:8848): (pescadillo ribosomal biogenesis factor 1) This gene encodes a nuclear protein that contains a breast cancer associated gene 1 (BRCA1) C-terminal interaction domain. The encoded protein interacts with BOP1 and WDR12 to form the PeBoW complex, which plays a critical role in cell proliferation via pre-rRNA processing and 60S ribosomal subunit maturation. Expression of this gene may play an important role in breast cancer proliferation and tumorigenicity. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Pseudogenes of this gene are located on the long arm of chromosome 4 and the short arm of chromosome 9. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 22-30607088-C-T is Benign according to our data. Variant chr22-30607088-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 341179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00722 (1100/152276) while in subpopulation SAS AF= 0.027 (130/4822). AF 95% confidence interval is 0.0232. There are 9 homozygotes in gnomad4. There are 534 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCN2	ENST00000450638.5	c.-420C>T		5_prime_UTR_variant	1/10	3
TCN2	ENST00000423350.1	n.86C>T		non_coding_transcript_exon_variant	1/2	2
PES1	ENST00000402281.5			upstream_gene_variant		2
PES1	ENST00000492986.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1098 AN: 152160 Hom.: 9 Cov.: 30

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00573

GnomAD4 exome AF: 0.0105 AC: 4726 AN: 448788 Hom.: 74 Cov.: 5 AF XY: 0.0119 AC XY: 2805 AN XY: 236684

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00399

Gnomad4 ASJ exome AF: 0.00343

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.0316

Gnomad4 FIN exome AF: 0.00475

Gnomad4 NFE exome AF: 0.00973

Gnomad4 OTH exome AF: 0.00925

GnomAD4 genome AF: 0.00722 AC: 1100 AN: 152276 Hom.: 9 Cov.: 30 AF XY: 0.00717 AC XY: 534 AN XY: 74440

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0270

Gnomad4 FIN AF: 0.00527

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00907 Hom.: 0

Bravo AF: 0.00655

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2021

- -

Transcobalamin II deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	8.2
Dann	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs143029449; hg19: chr22-31003075;