3-131535304-C-T

Variant names:

• chr3-131535304-C-T
• rs561689852
• NM_130808.3:c.1565G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_130808.3(CPNE4):​c.1565G>A​(p.Ser522Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CPNE4 NM_130808.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85
• Publications: 0 publications found

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]

ENSG00000306539 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14030722).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130808.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPNE4	NM_130808.3	MANE Select	c.1565G>A	p.Ser522Asn	missense	Exon 16 of 16	NP_570720.1	Q96A23-1
	CPNE4	NM_001289112.2		c.1619G>A	p.Ser540Asn	missense	Exon 16 of 16	NP_001276041.1	Q96A23-2
	CPNE4	NM_153429.2		c.1619G>A	p.Ser540Asn	missense	Exon 17 of 17	NP_702907.1	Q96A23-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPNE4	ENST00000429747.6	TSL:1 MANE Select	c.1565G>A	p.Ser522Asn	missense	Exon 16 of 16	ENSP00000411904.1	Q96A23-1
	CPNE4	ENST00000512332.5	TSL:1	c.1619G>A	p.Ser540Asn	missense	Exon 17 of 17	ENSP00000424853.1	Q96A23-2
	CPNE4	ENST00000511604.5	TSL:1	c.1565G>A	p.Ser522Asn	missense	Exon 19 of 19	ENSP00000423811.1	Q96A23-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249604 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461260 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726920

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.0000225 AC: 1 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111892

Other (OTH) AF: 0.0000331 AC: 2 AN: 60376

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74514

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.079
Sift	Benign	0.42	T
Sift4G	Benign	0.40	T
Polyphen		0.017	B
Vest4		0.47
MutPred		0.35		Loss of ubiquitination at K521 (P = 0.1016)
MVP		0.47
MPC		2.0
ClinPred		0.31	T
GERP RS		4.4
Varity_R		0.31
gMVP		0.57
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs561689852; hg19: chr3-131254148;