22-30607082-C-T

Variant names:

• chr22-30607082-C-T
• rs5753231
• ENST00000423350.1:n.80C>T

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.80C>T 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 0.165 in 591,184 control chromosomes in the GnomAD database, including 9,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1954 hom., cov: 30)
  • Exomes 𝑓: 0.17 (7628 hom.)
• Consequence: TCN2 ENST00000423350.1 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00900
• Publications: 22 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=-0.77).
• BP6: Variant 22-30607082-C-T is Benign according to our data. Variant chr22-30607082-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 369375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCN2	NM_000355.4	c.-250C>T		upstream_gene_variant		ENST00000215838.8	NP_000346.2
PES1	NM_001282327.1	c.-991G>A		upstream_gene_variant			NP_001269256.1
PES1	NM_001282328.1	c.-1038G>A		upstream_gene_variant			NP_001269257.1
TCN2	NM_001184726.2	c.-250C>T		upstream_gene_variant			NP_001171655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8	c.-250C>T		upstream_gene_variant		1	NM_000355.4	ENSP00000215838.3

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21627 AN: 152002 Hom.: 1954 Cov.: 30

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.150

GnomAD4 exome AF: 0.173 AC: 75877 AN: 439064 Hom.: 7628 Cov.: 5 AF XY: 0.169 AC XY: 38981 AN XY: 231174

African (AFR) AF: 0.0373 AC: 464 AN: 12434

American (AMR) AF: 0.122 AC: 2329 AN: 19100

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 3145 AN: 12926

East Asian (EAS) AF: 0.129 AC: 3700 AN: 28646

South Asian (SAS) AF: 0.102 AC: 4750 AN: 46466

European-Finnish (FIN) AF: 0.127 AC: 3265 AN: 25642

Middle Eastern (MID) AF: 0.148 AC: 277 AN: 1872

European-Non Finnish (NFE) AF: 0.201 AC: 53808 AN: 267370

Other (OTH) AF: 0.168 AC: 4139 AN: 24608

GnomAD4 genome AF: 0.142 AC: 21629 AN: 152120 Hom.: 1954 Cov.: 30 AF XY: 0.137 AC XY: 10193 AN XY: 74384

African (AFR) AF: 0.0407 AC: 1691 AN: 41512

American (AMR) AF: 0.128 AC: 1959 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 872 AN: 3470

East Asian (EAS) AF: 0.141 AC: 725 AN: 5158

South Asian (SAS) AF: 0.105 AC: 504 AN: 4818

European-Finnish (FIN) AF: 0.130 AC: 1380 AN: 10610

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14079 AN: 67952

Other (OTH) AF: 0.153 AC: 323 AN: 2108

Alfa AF: 0.181 Hom.: 5980

Bravo AF: 0.139

Asia WGS AF: 0.120 AC: 415 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Transcobalamin II deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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	-0.77
CADD	Benign	11
DANN	Benign	0.77
PhyloP100		0.0090
PromoterAI		-0.092	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: rs5753231; hg19: chr22-31003069;