3-131587576-C-G

Variant names:

• chr3-131587576-C-G
• NM_130808.3:c.688G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_130808.3(CPNE4):​c.688G>C​(p.Val230Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.42

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPNE4	NM_130808.3	c.688G>C	p.Val230Leu	missense_variant	Exon 8 of 16	ENST00000429747.6	NP_570720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPNE4	ENST00000429747.6	c.688G>C	p.Val230Leu	missense_variant	Exon 8 of 16	1	NM_130808.3	ENSP00000411904.1
CPNE4	ENST00000511604.5	c.688G>C	p.Val230Leu	missense_variant	Exon 11 of 19	1		ENSP00000423811.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.688G>C (p.V230L) alteration is located in exon 8 (coding exon 7) of the CPNE4 gene. This alteration results from a G to C substitution at nucleotide position 688, causing the valine (V) at amino acid position 230 to be replaced by a leucine (L). 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	0.90
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;.;T;.;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;.;.;.;.
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.3	M;.;M;.;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	N;.;N;N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D;.;D;D;D;D
Sift4G	Uncertain	0.017	D;T;D;T;D;T
Polyphen		0.83	P;P;P;P;P;P
Vest4		0.77
MutPred		0.61		Loss of catalytic residue at V230 (P = 0.0497);.;Loss of catalytic residue at V230 (P = 0.0497);.;Loss of catalytic residue at V230 (P = 0.0497);.;
MVP		0.74
MPC		0.39
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.60

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: chr3-131306420;