2-237088652-C-G

Position:

• chr2-237088652-C-G

Variant summary

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

The NM_006710.5(COPS8):​c.197C>G​(p.Ser66Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COPS8 NM_006710.5 missense, splice_region
• Scores: Splicing: ADA: 0.9818
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

Genes affected

COPS8 (HGNC:24335): (COP9 signalosome subunit 8) The protein encoded by this gene is one of the eight subunits of COP9 signalosome, a highly conserved protein complex that functions as an important regulator in multiple signaling pathways. The structure and function of COP9 signalosome is similar to that of the 19S regulatory particle of 26S proteasome. COP9 signalosome has been shown to interact with SCF-type E3 ubiquitin ligases and act as a positive regulator of E3 ubiquitin ligases. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COPS8	NM_006710.5	c.197C>G	p.Ser66Cys	missense_variant, splice_region_variant	3/8	ENST00000354371.7	NP_006701.1
COPS8	NM_198189.3	c.50C>G	p.Ser17Cys	missense_variant, splice_region_variant	4/9		NP_937832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COPS8	ENST00000354371.7	c.197C>G	p.Ser66Cys	missense_variant, splice_region_variant	3/8	1	NM_006710.5	ENSP00000346340	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The c.197C>G (p.S66C) alteration is located in exon 3 (coding exon 3) of the COPS8 gene. This alteration results from a C to G substitution at nucleotide position 197, causing the serine (S) at amino acid position 66 to be replaced by a cysteine (C). 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	0.13
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0070	D;.;D
Polyphen		0.99	D;.;.
Vest4		0.49
MutPred		0.45		Loss of disorder (P = 1e-04);.;Loss of disorder (P = 1e-04);
MVP		0.81
MPC		0.80
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.020		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: chr2-237997295;