3-131549991-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_130808.3(CPNE4):c.1258G>A(p.Val420Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPNE4 NM_130808.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15

Genes affected

CPNE4 (HGNC:2317): (copine 4) This gene belongs to the highly conserved copine family. It encodes a calcium-dependent, phospholipid-binding protein, which may be involved in membrane trafficking, mitogenesis and development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CPNE4
• BP4: Computational evidence support a benign effect (MetaRNN=0.28994787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPNE4	NM_130808.3	c.1258G>A	p.Val420Ile	missense_variant	14/16	ENST00000429747.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPNE4	ENST00000429747.6	c.1258G>A	p.Val420Ile	missense_variant	14/16	1	NM_130808.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 03, 2023

The c.1258G>A (p.V420I) alteration is located in exon 14 (coding exon 13) of the CPNE4 gene. This alteration results from a G to A substitution at nucleotide position 1258, causing the valine (V) at amino acid position 420 to be replaced by an isoleucine (I). 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	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.081	T;.;T;.;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;.;.;.;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.29	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.91	N;.;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.036	D;.;D;D;D;D
Sift4G	Uncertain	0.058	T;T;T;T;T;T
Polyphen		0.68	P;P;P;P;P;P
Vest4		0.21
MutPred		0.76		Gain of glycosylation at S423 (P = 0.0679);.;Gain of glycosylation at S423 (P = 0.0679);.;Gain of glycosylation at S423 (P = 0.0679);.;
MVP		0.16
MPC		1.9
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.27
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-131268835; COSMIC: COSV104714974;