rs756204866

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_014285.7(EXOSC2):​c.593G>A​(p.Gly198Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G198A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

EXOSC2
NM_014285.7 missense

Scores

11
7
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.66
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.967
PP5
Variant 9-130702231-G-A is Pathogenic according to our data. Variant chr9-130702231-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 446203.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EXOSC2NM_014285.7 linkuse as main transcriptc.593G>A p.Gly198Asp missense_variant 7/9 ENST00000372358.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EXOSC2ENST00000372358.10 linkuse as main transcriptc.593G>A p.Gly198Asp missense_variant 7/91 NM_014285.7 P1Q13868-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 10, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D;.;D;.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D
M_CAP
Uncertain
0.096
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D
MetaSVM
Uncertain
0.45
D
MutationAssessor
Pathogenic
3.6
H;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-6.3
D;D;D;D;D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.97
MutPred
0.87
Gain of catalytic residue at G198 (P = 0.0296);.;.;.;.;
MVP
0.68
MPC
1.0
ClinPred
0.99
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.95

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.

Other links and lift over

dbSNP: rs756204866; hg19: chr9-133577618; API