Variant 2-237094104-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006710.5(COPS8):c.346C>T(p.Arg116Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

COPS8
NM_006710.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.37

Variant links:

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]

COPS8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COPS8	NM_006710.5 linkuse as main transcript	c.346C>T	p.Arg116Cys	missense_variant	5/8	ENST00000354371.7	NP_006701.1
COPS8	NM_198189.3 linkuse as main transcript	c.199C>T	p.Arg67Cys	missense_variant	6/9		NP_937832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COPS8	ENST00000354371.7 linkuse as main transcript	c.346C>T	p.Arg116Cys	missense_variant	5/8	1	NM_006710.5	ENSP00000346340	P1	Q99627-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460916

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726706

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2023

The c.346C>T (p.R116C) alteration is located in exon 5 (coding exon 5) of the COPS8 gene. This alteration results from a C to T substitution at nucleotide position 346, causing the arginine (R) at amino acid position 116 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

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.84

T;D

M_CAP

Benign

0.0063

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Benign

0.28

Sift

Benign

0.079

T;T

Sift4G

Benign

0.084

T;.

Polyphen

0.087

B;.

Vest4

0.89

MutPred

0.74

Loss of MoRF binding (P = 0.0326);.;

MVP

0.62

MPC

0.64

ClinPred

0.96

GERP RS

3.4

Varity_R

0.59

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over