Genetic Variant NM_014285.7:c.58C>A (chr9-130693849-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014285.7(EXOSC2):c.58C>A(p.Arg20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,459,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R20R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

EXOSC2
NM_014285.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.901

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

EXOSC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047485977).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014285.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOSC2	NM_014285.7	MANE Select	c.58C>A	p.Arg20Ser	missense	Exon 1 of 9	NP_055100.2
EXOSC2	NM_001282708.1		c.58C>A	p.Arg20Ser	missense	Exon 1 of 8	NP_001269637.1	Q13868-2
EXOSC2	NM_001282709.1		c.58C>A	p.Arg20Ser	missense	Exon 1 of 8	NP_001269638.1	Q13868-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOSC2	ENST00000372358.10	TSL:1 MANE Select	c.58C>A	p.Arg20Ser	missense	Exon 1 of 9	ENSP00000361433.5	Q13868-1
EXOSC2	ENST00000851443.1		c.58C>A	p.Arg20Ser	missense	Exon 1 of 10	ENSP00000521502.1
EXOSC2	ENST00000495699.3	TSL:3	c.58C>A	p.Arg20Ser	missense	Exon 1 of 8	ENSP00000418463.3	A3KFL5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

250380

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000617

AC:

AN:

1459338

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.0000897

AC:

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110208

Other (OTH)

AF:

0.00

AC:

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0081

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.79

M_CAP

Benign

0.0032

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.66

PhyloP100

0.90

PrimateAI

Benign

0.48

PROVEAN

Benign

0.58

REVEL

Uncertain

0.31

Sift

Benign

0.67

Sift4G

Benign

0.72

Polyphen

0.0010

Vest4

0.34

MutPred

0.29

Gain of sheet (P = 0.0061)

MVP

0.092

MPC

0.28

ClinPred

0.20

GERP RS

6.2

PromoterAI

-0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.52

Mutation Taster

=88/12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over