9-130693804-A-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014285.7(EXOSC2):c.13A>C(p.Met5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,607,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

EXOSC2
NM_014285.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.81

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12630937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC2	NM_014285.7 link	c.13A>C	p.Met5Leu	missense_variant	Exon 1 of 9	ENST00000372358.10	NP_055100.2	Q13868-1
EXOSC2	NM_001282708.1 link	c.13A>C	p.Met5Leu	missense_variant	Exon 1 of 8		NP_001269637.1	Q13868-2
EXOSC2	NM_001282709.1 link	c.13A>C	p.Met5Leu	missense_variant	Exon 1 of 8		NP_001269638.1	Q13868-3
EXOSC2	NR_104230.1 link	n.45A>C		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.13A>C	p.Met5Leu	missense_variant	Exon 1 of 9	1	NM_014285.7	ENSP00000361433.5		Q13868-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

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

GnomAD3 exomes

AF:

0.0000322

AC:

AN:

248296

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134578

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000235

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1455282

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

723876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000113

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151794

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74098

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1062814). This variant has not been reported in the literature in individuals affected with EXOSC2-related conditions. This variant is present in population databases (rs763460421, gnomAD 0.02%). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the EXOSC2 protein (p.Met5Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.012

T;.;T;.;T

Eigen

Benign

-0.011

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Benign

0.0061

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.1

M;M;.;M;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.16

N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.069

T;T;T;T;T

Sift4G

Benign

0.21

T;T;T;T;T

Polyphen

0.0

B;.;.;.;.

Vest4

0.53

MutPred

0.20

Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.31

MPC

0.23

ClinPred

0.19

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.46

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