15-49133964-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004236.4(COPS2):c.860T>C(p.Met287Thr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COPS2 NM_004236.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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

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, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COPS2	NM_004236.4	c.860T>C	p.Met287Thr	missense_variant	8/13	ENST00000388901.10
COPS2	NM_001143887.2	c.881T>C	p.Met294Thr	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COPS2	ENST00000388901.10	c.860T>C	p.Met287Thr	missense_variant	8/13	1	NM_004236.4	P4
COPS2	ENST00000299259.10	c.881T>C	p.Met294Thr	missense_variant	8/13	1		A1
COPS2	ENST00000542928.5	c.668T>C	p.Met223Thr	missense_variant	6/11	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Nov 13, 2023

The c.881T>C (p.M294T) alteration is located in exon 8 (coding exon 8) of the COPS2 gene. This alteration results from a T to C substitution at nucleotide position 881, causing the methionine (M) at amino acid position 294 to be replaced by a threonine (T). 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	0.74
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Uncertain	0.64	D;.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.047	B;.;B
Vest4		0.84
MutPred		0.60		Loss of stability (P = 0.0269);.;.;
MVP		0.84
MPC		1.7
ClinPred		0.84	D
GERP RS		5.9
Varity_R		0.60
gMVP		0.88

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: chr15-49426161;