chr22-30607117-C-T

Variant names:

• chr22-30607117-C-T
• rs79083159
• ENST00000450638.5:c.-391C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000450638.5(TCN2):​c.-391C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 640,786 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (27 hom., cov: 30)
  • Exomes 𝑓: 0.0014 (7 hom.)
• Consequence: TCN2 ENST00000450638.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00300
• Publications: 2 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]

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

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 22-30607117-C-T is Benign according to our data. Variant chr22-30607117-C-T is described in ClinVar as [Benign]. Clinvar id is 341180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00927 (1412/152264) while in subpopulation AFR AF = 0.0318 (1320/41546). AF 95% confidence interval is 0.0303. There are 27 homozygotes in GnomAd4. There are 660 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.-215C>T		upstream_gene_variant		ENST00000215838.8	NP_000346.2
PES1	NM_001282327.1	c.-1026G>A		upstream_gene_variant			NP_001269256.1
PES1	NM_001282328.1	c.-1073G>A		upstream_gene_variant			NP_001269257.1
TCN2	NM_001184726.2	c.-215C>T		upstream_gene_variant			NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.-215C>T		upstream_gene_variant		1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1413 AN: 152146 Hom.: 27 Cov.: 30

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00815

GnomAD4 exome AF: 0.00138 AC: 675 AN: 488522 Hom.: 7 Cov.: 5 AF XY: 0.00111 AC XY: 286 AN XY: 258002

African (AFR) AF: 0.0287 AC: 405 AN: 14092

American (AMR) AF: 0.00307 AC: 80 AN: 26034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14916

East Asian (EAS) AF: 0.00 AC: 0 AN: 30760

South Asian (SAS) AF: 0.00 AC: 0 AN: 50678

European-Finnish (FIN) AF: 0.000173 AC: 5 AN: 28856

Middle Eastern (MID) AF: 0.00387 AC: 8 AN: 2066

European-Non Finnish (NFE) AF: 0.000279 AC: 82 AN: 294074

Other (OTH) AF: 0.00351 AC: 95 AN: 27046

GnomAD4 genome AF: 0.00927 AC: 1412 AN: 152264 Hom.: 27 Cov.: 30 AF XY: 0.00887 AC XY: 660 AN XY: 74430

African (AFR) AF: 0.0318 AC: 1320 AN: 41546

American (AMR) AF: 0.00320 AC: 49 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68010

Other (OTH) AF: 0.00806 AC: 17 AN: 2108

Alfa AF: 0.00335 Hom.: 5

Bravo AF: 0.0109

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Transcobalamin II deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.36
CADD	Benign	17
DANN	Benign	0.88
PhyloP100		-0.0030
PromoterAI		-0.058	Neutral
Mutation Taster		=300/0	polymorphism

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: rs79083159; hg19: chr22-31003104;