Genetic Variant CPNE5:p.Gly411Ser (chr6-36745485-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020939.2(CPNE5):c.1231G>A(p.Gly411Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,600,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

CPNE5
NM_020939.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

CPNE5 (HGNC:2318): (copine 5) Calcium-dependent membrane-binding proteins may regulate molecular events at the interface of the cell membrane and cytoplasm. This gene is one of several genes that encode a calcium-dependent protein containing two N-terminal type II C2 domains and an integrin A domain-like sequence in the C-terminus. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. More variants may exist, but their full-length natures could not be determined. [provided by RefSeq, Sep 2015]

CPNE5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPNE5	NM_020939.2 link	c.1231G>A	p.Gly411Ser	missense_variant	Exon 17 of 21	ENST00000244751.7	NP_065990.1	Q9HCH3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPNE5	ENST00000244751.7 link	c.1231G>A	p.Gly411Ser	missense_variant	Exon 17 of 21	1	NM_020939.2	ENSP00000244751.2		Q9HCH3-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000224

AC:

AN:

223614

Hom.:

AF XY:

0.0000166

AC XY:

AN XY:

120648

show subpopulations

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:

0.0000498

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000195

AC:

282

AN:

1448404

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

128

AN XY:

719120

show subpopulations

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:

0.000252

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1231G>A (p.G411S) alteration is located in exon 17 (coding exon 17) of the CPNE5 gene. This alteration results from a G to A substitution at nucleotide position 1231, causing the glycine (G) at amino acid position 411 to be replaced by a serine (S). 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

0.37

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

.;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Benign

-0.47

MutationAssessor

Pathogenic

3.5

.;H

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.97

.;D

Vest4

0.95

MutPred

0.69

.;Gain of disorder (P = 0.1127);

MVP

0.77

MPC

1.7

ClinPred

0.97

GERP RS

5.0

Varity_R

0.70

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over