chr15-49128027-C-T

Variant names:

• chr15-49128027-C-T
• rs1369277510
• NM_004236.4:c.1255G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004236.4(COPS2):​c.1255G>A​(p.Ala419Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A419G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COPS2 NM_004236.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21399397).

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.1255G>A	p.Ala419Thr	missense	Exon 13 of 13	NP_004227.1	P61201-1
	COPS2	NM_001143887.2		c.1276G>A	p.Ala426Thr	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.1255G>A	p.Ala419Thr	missense	Exon 13 of 13	ENSP00000373553.5	P61201-1
	COPS2	ENST00000299259.10	TSL:1	c.1276G>A	p.Ala426Thr	missense	Exon 13 of 13	ENSP00000299259.6	P61201-2
	COPS2	ENST00000940241.1		c.1273G>A	p.Ala425Thr	missense	Exon 13 of 13	ENSP00000610300.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.036
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.14
Sift	Benign	0.55	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.40
MutPred		0.25		Loss of catalytic residue at A419 (P = 0.0491)
MVP		0.47
MPC		0.41
ClinPred		0.78	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.47

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: rs1369277510; hg19: chr15-49420224;