19-18907038-A-G

Variant names:

• chr19-18907038-A-G
• NM_007263.4:c.365T>C

Variant summary

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

The NM_007263.4(COPE):​c.365T>C​(p.Met122Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COPE NM_007263.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.06
• 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]

ENSG00000268193 (HGNC:):

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.365T>C	p.Met122Thr	missense_variant	Exon 4 of 10	ENST00000262812.9	NP_009194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPE	ENST00000262812.9	c.365T>C	p.Met122Thr	missense_variant	Exon 4 of 10	1	NM_007263.4	ENSP00000262812.3
ENSG00000268193	ENST00000596918.5	n.*406T>C		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000469669.1
ENSG00000268193	ENST00000596918.5	n.*406T>C		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000469669.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.365T>C (p.M122T) alteration is located in exon 4 (coding exon 4) of the COPE gene. This alteration results from a T to C substitution at nucleotide position 365, causing the methionine (M) at amino acid position 122 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	Uncertain	0.51
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Benign	0.54
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.
PhyloP100		7.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;D;.
REVEL	Uncertain	0.29
Sift	Benign	0.10	T;T;.
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.67
MutPred		0.66		Loss of stability (P = 0.2014);Loss of stability (P = 0.2014);Loss of stability (P = 0.2014);
MVP		0.65
MPC		0.36
ClinPred		0.54	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.73
Mutation Taster		=35/65	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

hg19: chr19-19017847;