15-49133795-T-C

Variant names:

• chr15-49133795-T-C
• NM_004236.4:c.911A>G

Variant summary

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

The NM_004236.4(COPS2):​c.911A>G​(p.Asn304Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.98

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COPS2	NM_004236.4	c.911A>G	p.Asn304Ser	missense_variant	Exon 9 of 13	ENST00000388901.10	NP_004227.1
COPS2	NM_001143887.2	c.932A>G	p.Asn311Ser	missense_variant	Exon 9 of 13		NP_001137359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPS2	ENST00000388901.10	c.911A>G	p.Asn304Ser	missense_variant	Exon 9 of 13	1	NM_004236.4	ENSP00000373553.5
COPS2	ENST00000299259.10	c.932A>G	p.Asn311Ser	missense_variant	Exon 9 of 13	1		ENSP00000299259.6
COPS2	ENST00000542928.5	c.719A>G	p.Asn240Ser	missense_variant	Exon 7 of 11	2		ENSP00000443664.1
COPS2	ENST00000558843.5	c.*238A>G		downstream_gene_variant		1		ENSP00000452944.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.932A>G (p.N311S) alteration is located in exon 9 (coding exon 9) of the COPS2 gene. This alteration results from a A to G substitution at nucleotide position 932, causing the asparagine (N) at amino acid position 311 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.57	P;.;P
Vest4		0.71
MutPred		0.34		Loss of catalytic residue at N304 (P = 0.0273);.;.;
MVP		0.77
MPC		1.4
ClinPred		0.85	D
GERP RS		5.9
Varity_R		0.31
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr15-49425992;