9-130693813-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014285.7(EXOSC2):c.22C>G(p.Pro8Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00891 in 1,609,186 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P8L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (69 hom.)
• Consequence: EXOSC2 NM_014285.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.85

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038621426).
• BP6: Variant 9-130693813-C-G is Benign according to our data. Variant chr9-130693813-C-G is described in ClinVar as [Benign]. Clinvar id is 778382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00733 (1115/152170) while in subpopulation AMR AF= 0.0169 (258/15256). AF 95% confidence interval is 0.0152. There are 10 homozygotes in gnomad4. There are 550 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC2	NM_014285.7	c.22C>G	p.Pro8Ala	missense_variant	1/9	ENST00000372358.10
EXOSC2	NM_001282708.1	c.22C>G	p.Pro8Ala	missense_variant	1/8
EXOSC2	NM_001282709.1	c.22C>G	p.Pro8Ala	missense_variant	1/8
EXOSC2	NR_104230.1	n.54C>G		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC2	ENST00000372358.10	c.22C>G	p.Pro8Ala	missense_variant	1/9	1	NM_014285.7	P1

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1116 AN: 152052 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00425

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00707 AC: 1745 AN: 246954 Hom.: 13 AF XY: 0.00712 AC XY: 957 AN XY: 134324

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00843

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000853

Gnomad FIN exome AF: 0.00614

Gnomad NFE exome AF: 0.00982

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.00907 AC: 13215 AN: 1457016 Hom.: 69 Cov.: 33 AF XY: 0.00867 AC XY: 6286 AN XY: 725006

Gnomad4 AFR exome AF: 0.00150

Gnomad4 AMR exome AF: 0.00830

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000674

Gnomad4 FIN exome AF: 0.00707

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00871

GnomAD4 genome AF: 0.00733 AC: 1115 AN: 152170 Hom.: 10 Cov.: 32 AF XY: 0.00739 AC XY: 550 AN XY: 74398

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00425

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00888 Hom.: 6

Bravo AF: 0.00779

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00896 AC: 77

ExAC AF: 0.00641 AC: 776

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0114

EpiControl AF: 0.0106

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	EXOSC2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.024	T;.;T;.;T
Eigen	Benign	-0.0060
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
MetaRNN	Benign	0.0039	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	2.0	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.61	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.31	T;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.16	B;.;.;.;.
Vest4		0.53
MVP		0.42
MPC		0.25
ClinPred		0.057	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.62

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: rs148203698; hg19: chr9-133569200;