15-49155536-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004236.4(COPS2):c.43G>A(p.Asp15Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COPS2 NM_004236.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32943612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COPS2	NM_004236.4	c.43G>A	p.Asp15Asn	missense_variant	1/13	ENST00000388901.10
COPS2	NM_001143887.2	c.43G>A	p.Asp15Asn	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COPS2	ENST00000388901.10	c.43G>A	p.Asp15Asn	missense_variant	1/13	1	NM_004236.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727220

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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 22, 2023

The c.43G>A (p.D15N) alteration is located in exon 1 (coding exon 1) of the COPS2 gene. This alteration results from a G to A substitution at nucleotide position 43, causing the aspartic acid (D) at amino acid position 15 to be replaced by an asparagine (N). 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	0.29
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;T;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.72	D
LIST_S2	Pathogenic	0.99	D;D;T;D;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.3	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	D;D;N;D;N
REVEL	Benign	0.14
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;.;T
Polyphen		0.81	P;.;P;.;.
Vest4		0.70
MutPred		0.17		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.61
MPC		1.5
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.73
gMVP		0.18

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: chr15-49447733;