3-131535259-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_130808.3(CPNE4):c.1610G>A(p.Gly537Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPNE4 NM_130808.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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 1 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=0.17034718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPNE4	NM_130808.3	c.1610G>A	p.Gly537Asp	missense_variant	16/16	ENST00000429747.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPNE4	ENST00000429747.6	c.1610G>A	p.Gly537Asp	missense_variant	16/16	1	NM_130808.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461470 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727060

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Nov 15, 2021

The c.1610G>A (p.G537D) alteration is located in exon 16 (coding exon 15) of the CPNE4 gene. This alteration results from a G to A substitution at nucleotide position 1610, causing the glycine (G) at amino acid position 537 to be replaced by an aspartic acid (D). 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	0.44
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.020	T;.;T;.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;.;.;.;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N;.;N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.080	N;.;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.33	T;.;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T
Polyphen		0.046	B;B;B;B;B;B
Vest4		0.31
MutPred		0.35		Gain of glycosylation at Y534 (P = 0.0101);.;Gain of glycosylation at Y534 (P = 0.0101);.;Gain of glycosylation at Y534 (P = 0.0101);.;
MVP		0.21
MPC		1.3
ClinPred		0.54	D
GERP RS		5.3
Varity_R		0.31
gMVP		0.65

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: chr3-131254103;