9-130693849-C-T

Variant names:

• chr9-130693849-C-T
• rs140638723
• NM_014285.7:c.58C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014285.7(EXOSC2):​c.58C>T​(p.Arg20Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EXOSC2 NM_014285.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.901
• Publications: 3 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1539818).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC2	NM_014285.7	MANE Select	c.58C>T	p.Arg20Cys	missense	Exon 1 of 9	NP_055100.2
	EXOSC2	NM_001282708.1		c.58C>T	p.Arg20Cys	missense	Exon 1 of 8	NP_001269637.1	Q13868-2
	EXOSC2	NM_001282709.1		c.58C>T	p.Arg20Cys	missense	Exon 1 of 8	NP_001269638.1	Q13868-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC2	ENST00000372358.10	TSL:1 MANE Select	c.58C>T	p.Arg20Cys	missense	Exon 1 of 9	ENSP00000361433.5	Q13868-1
	EXOSC2	ENST00000851443.1		c.58C>T	p.Arg20Cys	missense	Exon 1 of 10	ENSP00000521502.1
	EXOSC2	ENST00000495699.3	TSL:3	c.58C>T	p.Arg20Cys	missense	Exon 1 of 8	ENSP00000418463.3	A3KFL5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151682 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000320 AC: 8 AN: 250380 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1459338 Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12 AN XY: 726138

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1110206

Other (OTH) AF: 0.0000166 AC: 1 AN: 60194

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151682 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74042

African (AFR) AF: 0.00 AC: 0 AN: 41262

American (AMR) AF: 0.00 AC: 0 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.017
Eigen_PC	Benign	0.0060
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.90
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.20
Sift	Benign	0.042	D
Sift4G	Uncertain	0.051	T
Polyphen		0.88	P
Vest4		0.62
MVP		0.31
MPC		0.47
ClinPred		0.34	T
GERP RS		6.2
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.56
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs140638723; hg19: chr9-133569236;