chr8-86528639-G-A

Position:

• chr8-86528639-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003909.5(CPNE3):​c.94G>A​(p.Val32Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CPNE3 NM_003909.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.12

Genes affected

CPNE3 (HGNC:2316): (copine 3) Calcium-dependent membrane-binding proteins may regulate molecular events at the interface of the cell membrane and cytoplasm. This gene encodes a protein which contains two type II C2 domains in the amino-terminus and an A domain-like sequence in the carboxy-terminus. The A domain mediates interactions between integrins and extracellular ligands. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPNE3	NM_003909.5	c.94G>A	p.Val32Met	missense_variant	3/17	ENST00000517490.6	NP_003900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPNE3	ENST00000517490.6	c.94G>A	p.Val32Met	missense_variant	3/17	1	NM_003909.5	ENSP00000477590.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2024

The c.94G>A (p.V32M) alteration is located in exon 3 (coding exon 1) of the CPNE3 gene. This alteration results from a G to A substitution at nucleotide position 94, causing the valine (V) at amino acid position 32 to be replaced by a methionine (M). 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	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T;T;T;.;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	.;.;.;.;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	.;.;.;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.42
MutPred		0.54		Gain of disorder (P = 0.1789);Gain of disorder (P = 0.1789);Gain of disorder (P = 0.1789);Gain of disorder (P = 0.1789);Gain of disorder (P = 0.1789);Gain of disorder (P = 0.1789);
MVP		0.65
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs1820595453; hg19: chr8-87540867;