chr15-49128027-C-A

Variant names:

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

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>T​(p.Ala419Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COPS2 NM_004236.4 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.16242293).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COPS2	NM_004236.4	c.1255G>T	p.Ala419Ser	missense_variant	Exon 13 of 13	ENST00000388901.10	NP_004227.1
COPS2	NM_001143887.2	c.1276G>T	p.Ala426Ser	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>T	p.Ala419Ser	missense_variant	Exon 13 of 13	1	NM_004236.4	ENSP00000373553.5
COPS2	ENST00000299259.10	c.1276G>T	p.Ala426Ser	missense_variant	Exon 13 of 13	1		ENSP00000299259.6
COPS2	ENST00000542928.5	c.1063G>T	p.Ala355Ser	missense_variant	Exon 11 of 11	2		ENSP00000443664.1
COPS2	ENST00000560240.5	n.138+1450G>T		intron_variant	Intron 2 of 3	4		ENSP00000453546.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251172 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461670 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727136

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Benign	0.81
DEOGEN2	Benign	0.10	T;.;T
Eigen	Benign	0.0078
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.73	T;T;T
Sift4G	Benign	0.73	T;T;T
Polyphen		0.0020	B;.;B
Vest4		0.27
MutPred		0.29		Gain of disorder (P = 0.0349);.;.;
MVP		0.47
MPC		0.39
ClinPred		0.32	T
GERP RS		5.9
Varity_R		0.32
gMVP		0.41

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;