15-49128023-C-G

Variant names:

• chr15-49128023-C-G
• rs377183837
• NM_004236.4:c.1259G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004236.4(COPS2):​c.1259G>C​(p.Arg420Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R420Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COPS2 NM_004236.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86
• Publications: 2 publications found

Genes affected

COPS2 (HGNC:30747): (COP9 signalosome subunit 2) Predicted to enable transcription corepressor activity. Involved in protein deneddylation and protein phosphorylation. Located in cytoplasm. Part of COP9 signalosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004236.4. 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
	COPS2	NM_004236.4	MANE Select	c.1259G>C	p.Arg420Pro	missense	Exon 13 of 13	NP_004227.1	P61201-1
	COPS2	NM_001143887.2		c.1280G>C	p.Arg427Pro	missense	Exon 13 of 13	NP_001137359.1	P61201-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COPS2	ENST00000388901.10	TSL:1 MANE Select	c.1259G>C	p.Arg420Pro	missense	Exon 13 of 13	ENSP00000373553.5	P61201-1
	COPS2	ENST00000299259.10	TSL:1	c.1280G>C	p.Arg427Pro	missense	Exon 13 of 13	ENSP00000299259.6	P61201-2
	COPS2	ENST00000940241.1		c.1277G>C	p.Arg426Pro	missense	Exon 13 of 13	ENSP00000610300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.97	D
Vest4		0.88
MutPred		0.62		Loss of MoRF binding (P = 0.0141)
MVP		0.54
MPC		1.4
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.96

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: rs377183837; hg19: chr15-49420220;