9-130693880-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.60

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]

ACMG classification

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: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC2	NM_014285.7	c.89G>T	p.Gly30Val	missense_variant	1/9	ENST00000372358.10
EXOSC2	NM_001282708.1	c.89G>T	p.Gly30Val	missense_variant	1/8
EXOSC2	NM_001282709.1	c.89G>T	p.Gly30Val	missense_variant	1/8
EXOSC2	NR_104230.1	n.121G>T		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC2	ENST00000372358.10	c.89G>T	p.Gly30Val	missense_variant	1/9	1	NM_014285.7	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152076 Hom.: 0 Cov.: 32

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: 4 AN: 250596 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135560

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: 30 AN: 1459900 Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18 AN XY: 726252

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: 8 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74296

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.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	EXOSC2: PP3, PS3:Supporting, PS4:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	33
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	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	4.0	H;H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
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	D
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

Other links and lift over

dbSNP: rs537467155; hg19: chr9-133569267;