Genetic Variant COPE:p.Ala139Gly (chr19-18906987-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_007263.4(COPE):c.416C>G(p.Ala139Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,421,044 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. A139V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

COPE
NM_007263.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.52

Publications

2 publications found

Variant links:

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]

COPE links:

ENSG00000268193 (HGNC:):

ENSG00000268193 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41634914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COPE	NM_007263.4 link	c.416C>G	p.Ala139Gly	missense_variant	Exon 4 of 10	ENST00000262812.9	NP_009194.2	O14579-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPE	ENST00000262812.9 link	c.416C>G	p.Ala139Gly	missense_variant	Exon 4 of 10	1	NM_007263.4	ENSP00000262812.3		O14579-1
ENSG00000268193	ENST00000596918.5 link	n.*457C>G		downstream_gene_variant		5		ENSP00000469669.1		M0R1B8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1421044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32630

American (AMR)

AF:

0.00

AC:

AN:

38280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25360

East Asian (EAS)

AF:

0.00

AC:

AN:

37526

South Asian (SAS)

AF:

0.00

AC:

AN:

81316

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091692

Other (OTH)

AF:

0.0000170

AC:

AN:

58840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

T;.;.

Eigen

Benign

0.037

Eigen_PC

Benign

0.097

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.42

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

L;L;.

PhyloP100

9.5

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.5

D;D;.

REVEL

Benign

0.13

Sift

Benign

0.29

T;D;.

Sift4G

Benign

0.32

T;T;T

Polyphen

0.46

P;.;.

Vest4

0.38

MutPred

0.51

Loss of stability (P = 0.0489);Loss of stability (P = 0.0489);Loss of stability (P = 0.0489);

MVP

0.47

MPC

0.29

ClinPred

0.69

GERP RS

4.8

Varity_R

0.58

gMVP

0.19

Mutation Taster

=64/36

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over