rs748210508

Variant names:

• chr19-18904797-C-A
• rs748210508
• NM_007263.4:c.553G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-18904797-C-A
• chr19-18904797-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007263.4(COPE):​c.553G>T​(p.Ala185Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A185T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: COPE NM_007263.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.58
• Publications: 0 publications found

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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COPE	NM_007263.4	c.553G>T	p.Ala185Ser	missense_variant	Exon 6 of 10	ENST00000262812.9	NP_009194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPE	ENST00000262812.9	c.553G>T	p.Ala185Ser	missense_variant	Exon 6 of 10	1	NM_007263.4	ENSP00000262812.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402260 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 692092

African (AFR) AF: 0.00 AC: 0 AN: 31714

American (AMR) AF: 0.0000276 AC: 1 AN: 36284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25192

East Asian (EAS) AF: 0.00 AC: 0 AN: 35936

South Asian (SAS) AF: 0.00 AC: 0 AN: 79394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080706

Other (OTH) AF: 0.00 AC: 0 AN: 58104

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	M;M;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.4	N;N;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.15	T;T;.;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.74	P;.;.;.
Vest4		0.64
MutPred		0.89		Gain of disorder (P = 0.0974);Gain of disorder (P = 0.0974);.;.;
MVP		0.59
MPC		0.51
ClinPred		0.94	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.70
gMVP		0.41
Mutation Taster		=12/88	disease causing

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: rs748210508; hg19: chr19-19015606;