ENST00000423350.1:n.149A>G

Variant names:

• chr22-30607151-A-G
• rs2240433
• ENST00000423350.1:n.149A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000423350.1(TCN2):​n.149A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 658,624 control chromosomes in the GnomAD database, including 108,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31863 hom., cov: 29)
  • Exomes 𝑓: 0.54 (77078 hom.)
• Consequence: TCN2 ENST00000423350.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.802
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 22-30607151-A-G is Benign according to our data. Variant chr22-30607151-A-G is described in ClinVar as [Benign]. Clinvar id is 341183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.-181A>G		upstream_gene_variant		ENST00000215838.8	NP_000346.2
PES1	NM_001282327.1	c.-1060T>C		upstream_gene_variant			NP_001269256.1
PES1	NM_001282328.1	c.-1107T>C		upstream_gene_variant			NP_001269257.1
TCN2	NM_001184726.2	c.-181A>G		upstream_gene_variant			NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.-181A>G		upstream_gene_variant		1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96039 AN: 151394 Hom.: 31826 Cov.: 29

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.619

GnomAD4 exome AF: 0.536 AC: 271744 AN: 507116 Hom.: 77078 Cov.: 6 AF XY: 0.527 AC XY: 141705 AN XY: 268870

African (AFR) AF: 0.821 AC: 11922 AN: 14530

American (AMR) AF: 0.520 AC: 15426 AN: 29674

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 8935 AN: 15850

East Asian (EAS) AF: 0.243 AC: 7470 AN: 30804

South Asian (SAS) AF: 0.390 AC: 21077 AN: 54084

European-Finnish (FIN) AF: 0.604 AC: 17426 AN: 28860

Middle Eastern (MID) AF: 0.566 AC: 1217 AN: 2150

European-Non Finnish (NFE) AF: 0.569 AC: 172729 AN: 303452

Other (OTH) AF: 0.561 AC: 15542 AN: 27712

GnomAD4 genome AF: 0.634 AC: 96129 AN: 151508 Hom.: 31863 Cov.: 29 AF XY: 0.630 AC XY: 46621 AN XY: 73998

African (AFR) AF: 0.822 AC: 34012 AN: 41362

American (AMR) AF: 0.581 AC: 8852 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1960 AN: 3470

East Asian (EAS) AF: 0.267 AC: 1358 AN: 5092

South Asian (SAS) AF: 0.386 AC: 1840 AN: 4762

European-Finnish (FIN) AF: 0.613 AC: 6434 AN: 10492

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.585 AC: 39626 AN: 67794

Other (OTH) AF: 0.615 AC: 1295 AN: 2104

Alfa AF: 0.598 Hom.: 10517

Bravo AF: 0.638

Asia WGS AF: 0.394 AC: 1376 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Transcobalamin II deficiency Benign:1

Jan 12, 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	-0.79
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.80
PromoterAI		0.17	Neutral
Mutation Taster		=300/0	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: rs2240433; hg19: chr22-31003138;