19-18905577-G-A

Variant names:

• chr19-18905577-G-A
• rs536383915
• NM_007263.4:c.496C>T

Variant summary

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

The NM_007263.4(COPE):​c.496C>T​(p.Arg166Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,590,608 control chromosomes in the GnomAD database, including 1 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R166G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (1 hom.)
• Consequence: COPE NM_007263.4 missense, splice_region
• Scores: Splicing: ADA: 0.03735
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

Genes affected

COPE (HGNC:2234): (COPI coat complex subunit epsilon) The product of this gene is an epsilon subunit of coatomer protein complex. Coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles. It is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. Coatomer complex consists of at least the alpha, beta, beta', gamma, delta, epsilon and zeta subunits. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
COPE	NM_007263.4	c.496C>T	p.Arg166Trp	missense_variant, splice_region_variant	Exon 5 of 10	ENST00000262812.9	NP_009194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPE	ENST00000262812.9	c.496C>T	p.Arg166Trp	missense_variant, splice_region_variant	Exon 5 of 10	1	NM_007263.4	ENSP00000262812.3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000543 AC: 12 AN: 221108 AF XY: 0.0000500

Gnomad AFR exome AF: 0.000136

Gnomad AMR exome AF: 0.0000627

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000955

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000202 AC: 29 AN: 1438342 Hom.: 1 Cov.: 31 AF XY: 0.0000196 AC XY: 14 AN XY: 714812

African (AFR) AF: 0.000180 AC: 6 AN: 33368

American (AMR) AF: 0.0000469 AC: 2 AN: 42686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25704

East Asian (EAS) AF: 0.00 AC: 0 AN: 39062

South Asian (SAS) AF: 0.000155 AC: 13 AN: 84028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1108312

Other (OTH) AF: 0.0000167 AC: 1 AN: 59940

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74432

African (AFR) AF: 0.000144 AC: 6 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.496C>T (p.R166W) alteration is located in exon 5 (coding exon 5) of the COPE gene. This alteration results from a C to T substitution at nucleotide position 496, causing the arginine (R) at amino acid position 166 to be replaced by a tryptophan (W). 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	0.010	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.8	M;M;.;.
PhyloP100		2.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.0	D;D;.;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.56
MutPred		0.59		Loss of disorder (P = 0.002);Loss of disorder (P = 0.002);.;.;
MVP		0.67
MPC		0.27
ClinPred		0.88	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.86
gMVP		0.42
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.037
dbscSNV1_RF	Benign	0.27
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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs536383915; hg19: chr19-19016386; COSMIC: COSV53229642; COSMIC: COSV53229642;