3-131723603-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_130808.3(CPNE4):c.203G>A(p.Arg68His) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,486 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CPNE4 NM_130808.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CPNE4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPNE4	NM_130808.3	c.203G>A	p.Arg68His	missense_variant	3/16	ENST00000429747.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPNE4	ENST00000429747.6	c.203G>A	p.Arg68His	missense_variant	3/16	1	NM_130808.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251158 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461486 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000113

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

Dec 22, 2023

The c.203G>A (p.R68H) alteration is located in exon 3 (coding exon 2) of the CPNE4 gene. This alteration results from a G to A substitution at nucleotide position 203, causing the arginine (R) at amino acid position 68 to be replaced by a histidine (H). 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	0.17
BayesDel_addAF	Benign	0.0049	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;.;T;.;T;.;.;T;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;.;.;.;.;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Uncertain	2.1	M;.;M;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;.;D;D;D;D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.027	D;.;D;D;D;D;D;T;D
Sift4G	Uncertain	0.042	D;T;D;T;D;T;D;.;.
Polyphen		1.0	D;D;D;D;D;D;.;.;.
Vest4		0.69
MutPred		0.44		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.47
MPC		0.91
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.39
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs1343320693; hg19: chr3-131442447; COSMIC: COSV70189858;