rs148203698

Variant names:

• chr9-130693813-C-G
• rs148203698
• NM_014285.7:c.22C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-130693813-C-G
• chr9-130693813-C-T
• chr9-130693813-C-A

Variant summary

Our verdict is Benign. The variant received -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P8S) 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/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.85
• Publications: 6 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: Benign. The variant received -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/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.22C>G	p.Pro8Ala	missense	Exon 1 of 9	NP_055100.2
	EXOSC2	NM_001282708.1		c.22C>G	p.Pro8Ala	missense	Exon 1 of 8	NP_001269637.1	Q13868-2
	EXOSC2	NM_001282709.1		c.22C>G	p.Pro8Ala	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.22C>G	p.Pro8Ala	missense	Exon 1 of 9	ENSP00000361433.5	Q13868-1
	EXOSC2	ENST00000851443.1		c.22C>G	p.Pro8Ala	missense	Exon 1 of 10	ENSP00000521502.1
	EXOSC2	ENST00000495699.3	TSL:3	c.22C>G	p.Pro8Ala	missense	Exon 1 of 8	ENSP00000418463.3	A3KFL5

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

GnomAD2 exomes AF: 0.00707 AC: 1745 AN: 246954 AF XY: 0.00712

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 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

African (AFR) AF: 0.00150 AC: 50 AN: 33356

American (AMR) AF: 0.00830 AC: 369 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 317 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.000674 AC: 58 AN: 86100

European-Finnish (FIN) AF: 0.00707 AC: 373 AN: 52776

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5750

European-Non Finnish (NFE) AF: 0.0103 AC: 11464 AN: 1108998

Other (OTH) AF: 0.00871 AC: 523 AN: 60054

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

African (AFR) AF: 0.00159 AC: 66 AN: 41526

American (AMR) AF: 0.0169 AC: 258 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00425 AC: 45 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0100 AC: 681 AN: 68010

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.0060
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.13
Sift	Benign	0.31	T
Sift4G	Benign	0.46	T
Polyphen		0.16	B
Vest4		0.53
MVP		0.42
MPC		0.25
ClinPred		0.057	T
GERP RS		6.1
PromoterAI		0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.62
Mutation Taster		=99/1	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: rs148203698; hg19: chr9-133569200; COSMIC: COSV106109559;