9-130693880-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_014285.7(EXOSC2):c.89G>T(p.Gly30Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,611,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

EXOSC2
NM_014285.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 8.60

Variant links:

Genes affected

EXOSC2 (HGNC:17097): (exosome component 2) Predicted to enable RNA binding activity. Involved in positive regulation of cell growth. Located in cytoplasm; nucleolus; and nucleoplasm. Part of nuclear exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

EXOSC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

PP5

Variant 9-130693880-G-T is Pathogenic according to our data. Variant chr9-130693880-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446202.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC2	NM_014285.7 link	c.89G>T	p.Gly30Val	missense_variant	Exon 1 of 9	ENST00000372358.10	NP_055100.2	Q13868-1
EXOSC2	NM_001282708.1 link	c.89G>T	p.Gly30Val	missense_variant	Exon 1 of 8		NP_001269637.1	Q13868-2
EXOSC2	NM_001282709.1 link	c.89G>T	p.Gly30Val	missense_variant	Exon 1 of 8		NP_001269638.1	Q13868-3
EXOSC2	NR_104230.1 link	n.121G>T		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC2	ENST00000372358.10 link	c.89G>T	p.Gly30Val	missense_variant	Exon 1 of 9	1	NM_014285.7	ENSP00000361433.5		Q13868-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250596

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1459900

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726252

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome

Pathogenic:3Uncertain:1

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.89G>T;p.(Gly30Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 446202; OMIM: 602238.0001; PMID: 26843489) - PS4.The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 26843489) - PS2.The variant is present at low allele frequencies population databases (rs537467155– gnomAD 0.0005261%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly30Val) was detected in trans with a pathogenic variant (PMID: 26843489) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 26843489) - PP1_moderate. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Oct 02, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 29, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 28, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3_SUP,PM2,PM3,PP3 -

not provided

Pathogenic:1Uncertain:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 30 of the EXOSC2 protein (p.Gly30Val). This variant is present in population databases (rs537467155, gnomAD 0.004%). This missense change has been observed in individuals with EXOSC2-related conditions (PMID: 26843489). ClinVar contains an entry for this variant (Variation ID: 446202). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EXOSC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EXOSC2 function (PMID: 31628467, 34162742). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EXOSC2: PM2, PM3, PP3, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;D;.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Benign

0.074

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Pathogenic

4.0

H;H;.;H;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.9

D;D;D;D;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

1.0

MVP

0.67

MPC

1.0

ClinPred

1.0

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over