9-130693828-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014285.7(EXOSC2):c.37C>T(p.Pro13Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EXOSC2 NM_014285.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055711627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC2	NM_014285.7	c.37C>T	p.Pro13Ser	missense_variant	1/9	ENST00000372358.10
EXOSC2	NM_001282708.1	c.37C>T	p.Pro13Ser	missense_variant	1/8
EXOSC2	NM_001282709.1	c.37C>T	p.Pro13Ser	missense_variant	1/8
EXOSC2	NR_104230.1	n.69C>T		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC2	ENST00000372358.10	c.37C>T	p.Pro13Ser	missense_variant	1/9	1	NM_014285.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248830 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134964

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458424 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 31, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 13 of the EXOSC2 protein (p.Pro13Ser). This variant is present in population databases (rs780803058, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with EXOSC2-related conditions. 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. 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	Benign	0.073
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	19
Dann	Benign	0.89
DEOGEN2	Benign	0.013	T;.;T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.056	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.60	N;N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.16	N;N;N;N;N
REVEL	Benign	0.083
Sift	Benign	0.55	T;T;T;T;T
Sift4G	Benign	0.80	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.22
MutPred		0.22		Gain of phosphorylation at P13 (P = 0.0113);Gain of phosphorylation at P13 (P = 0.0113);Gain of phosphorylation at P13 (P = 0.0113);Gain of phosphorylation at P13 (P = 0.0113);Gain of phosphorylation at P13 (P = 0.0113);
MVP		0.22
MPC		0.25
ClinPred		0.17	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.45

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: rs780803058; hg19: chr9-133569215;