9-130693825-A-G

Variant names:

• chr9-130693825-A-G
• NM_014285.7:c.34A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014285.7(EXOSC2):​c.34A>G​(p.Lys12Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXOSC2 NM_014285.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12381372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC2	NM_014285.7	c.34A>G	p.Lys12Glu	missense_variant	Exon 1 of 9	ENST00000372358.10	NP_055100.2
EXOSC2	NM_001282708.1	c.34A>G	p.Lys12Glu	missense_variant	Exon 1 of 8		NP_001269637.1
EXOSC2	NM_001282709.1	c.34A>G	p.Lys12Glu	missense_variant	Exon 1 of 8		NP_001269638.1
EXOSC2	NR_104230.1	n.66A>G		non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC2	ENST00000372358.10	c.34A>G	p.Lys12Glu	missense_variant	Exon 1 of 9	1	NM_014285.7	ENSP00000361433.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34A>G (p.K12E) alteration is located in exon 1 (coding exon 1) of the EXOSC2 gene. This alteration results from a A to G substitution at nucleotide position 34, causing the lysine (K) at amino acid position 12 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.023	T;.;T;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.77	T;T;T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M;M;.;M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.18	T;T;T;T;T
Sift4G	Benign	0.80	T;T;T;T;T
Polyphen		0.0070	B;.;.;.;.
Vest4		0.27
MutPred		0.26		Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);
MVP		0.26
MPC		0.34
ClinPred		0.58	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-133569212;