15-49128027-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. Variant has been reported in ClinVar 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

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 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COPS2	NM_004236.4	c.1255G>A	p.Ala419Thr	missense_variant	Exon 13 of 13	ENST00000388901.10	NP_004227.1
COPS2	NM_001143887.2	c.1276G>A	p.Ala426Thr	missense_variant	Exon 13 of 13		NP_001137359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPS2	ENST00000388901.10	c.1255G>A	p.Ala419Thr	missense_variant	Exon 13 of 13	1	NM_004236.4	ENSP00000373553.5
COPS2	ENST00000299259.10	c.1276G>A	p.Ala426Thr	missense_variant	Exon 13 of 13	1		ENSP00000299259.6
COPS2	ENST00000542928.5	c.1063G>A	p.Ala355Thr	missense_variant	Exon 11 of 11	2		ENSP00000443664.1
COPS2	ENST00000560240.5	n.138+1450G>A		intron_variant	Intron 2 of 3	4		ENSP00000453546.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1276G>A (p.A426T) alteration is located in exon 13 (coding exon 13) of the COPS2 gene. This alteration results from a G to A substitution at nucleotide position 1276, causing the alanine (A) at amino acid position 426 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	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;.;T
Eigen	Benign	0.036
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.84	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.55	T;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.0010	B;.;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

Publications

LitVar

Other links and lift over

dbSNP: rs1369277510; hg19: chr15-49420224;