Genetic Variant TCN2:n.139G>C (chr22-30607141-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000423350.1(TCN2):n.139G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000041 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TCN2
ENST00000423350.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.109

Publications

0 publications found

Variant links:

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 links:

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]

PES1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
TCN2	NM_000355.4 link	c.-191G>C	upstream_gene_variant	ENST00000215838.8	NP_000346.2	P20062-1
PES1	NM_001282327.1 link	c.-1050C>G	upstream_gene_variant		NP_001269256.1	F6VXF5
PES1	NM_001282328.1 link	c.-1097C>G	upstream_gene_variant		NP_001269257.1	F6VXF5B3KTZ6
TCN2	NM_001184726.2 link	c.-191G>C	upstream_gene_variant		NP_001171655.1	P20062-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCN2	ENST00000215838.8 link	c.-191G>C		upstream_gene_variant		1	NM_000355.4	ENSP00000215838.3		P20062-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151346

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000415

AC:

AN:

482400

Hom.:

Cov.:

AF XY:

0.0000470

AC XY:

AN XY:

255174

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

14008

American (AMR)

AF:

0.00

AC:

AN:

27464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14926

East Asian (EAS)

AF:

0.00

AC:

AN:

29914

South Asian (SAS)

AF:

0.00

AC:

AN:

51598

European-Finnish (FIN)

AF:

0.0000744

AC:

AN:

26880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2038

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

289174

Other (OTH)

AF:

0.0000379

AC:

AN:

26398

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.270

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

151346

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73880

African (AFR)

AF:

0.00

AC:

AN:

41130

American (AMR)

AF:

0.00

AC:

AN:

15158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67854

Other (OTH)

AF:

0.00

AC:

AN:

2068

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.4

(source)

DANN

Benign

0.62

PhyloP100

-0.11

PromoterAI

0.076

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

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

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chr22-30607141-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over