9-130693855-A-C

Variant names:

• chr9-130693855-A-C
• rs772506400
• NM_014285.7:c.64A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014285.7(EXOSC2):​c.64A>C​(p.Thr22Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T22S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: EXOSC2 NM_014285.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.636
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024290174).

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.64A>C	p.Thr22Pro	missense	Exon 1 of 9	NP_055100.2
	EXOSC2	NM_001282708.1		c.64A>C	p.Thr22Pro	missense	Exon 1 of 8	NP_001269637.1	Q13868-2
	EXOSC2	NM_001282709.1		c.64A>C	p.Thr22Pro	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.64A>C	p.Thr22Pro	missense	Exon 1 of 9	ENSP00000361433.5	Q13868-1
	EXOSC2	ENST00000851443.1		c.64A>C	p.Thr22Pro	missense	Exon 1 of 10	ENSP00000521502.1
	EXOSC2	ENST00000495699.3	TSL:3	c.64A>C	p.Thr22Pro	missense	Exon 1 of 8	ENSP00000418463.3	A3KFL5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 250676 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460504 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726594

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.000202 AC: 9 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111010

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.65
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.64
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.054
Sift	Benign	0.32	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.33		Loss of phosphorylation at T22 (P = 0.0047)
MVP		0.040
MPC		0.31
ClinPred		0.052	T
GERP RS		-1.3
PromoterAI		0.068	Neutral
Varity_R		0.43
gMVP		0.50
Mutation Taster		=88/12	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: rs772506400; hg19: chr9-133569242;