rs2425068

Variant names:

• chr20-35626801-T-C
• rs2425068
• NM_152925.3:c.1239A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The ENST00000437340.5(CPNE1):​c.1237-1A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0612 in 1,613,150 control chromosomes in the GnomAD database, including 3,430 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.047 (261 hom., cov: 31)
  • Exomes 𝑓: 0.063 (3169 hom.)
• Consequence: CPNE1 ENST00000437340.5 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.13
• Publications: 24 publications found

Genes affected

CPNE1 (HGNC:2314): (copine 1) Calcium-dependent membrane-binding proteins may regulate molecular events at the interface of the cell membrane and cytoplasm. This gene encodes a calcium-dependent protein that also contains two N-terminal type II C2 domains and an integrin A domain-like sequence in the C-terminus. However, the encoded protein does not contain a predicted signal sequence or transmembrane domains. This protein has a broad tissue distribution and it may function in membrane trafficking. This gene and the gene for RNA binding motif protein 12 overlap at map location 20q11.21. Alternate splicing results in multiple transcript variants encoding different proteins. [provided by RefSeq, Aug 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.14625 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.2, offset of 0 (no position change), new splice context is: aatgggcttgtccccagcAGtac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000437340.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPNE1	NM_152925.3	MANE Select	c.1239A>G	p.Gln413Gln	splice_region synonymous	Exon 15 of 16	NP_690902.1
	CPNE1	NM_003915.6		c.1254A>G	p.Gln418Gln	splice_region synonymous	Exon 15 of 16	NP_003906.2
	CPNE1	NM_152926.3		c.1239A>G	p.Gln413Gln	splice_region synonymous	Exon 15 of 16	NP_690903.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPNE1	ENST00000397443.7	TSL:5 MANE Select	c.1239A>G	p.Gln413Gln	splice_region synonymous	Exon 15 of 16	ENSP00000380585.1
	CPNE1	ENST00000317677.9	TSL:1	c.1254A>G	p.Gln418Gln	splice_region synonymous	Exon 15 of 16	ENSP00000317257.5
	CPNE1	ENST00000352393.8	TSL:1	c.1239A>G	p.Gln413Gln	splice_region synonymous	Exon 17 of 18	ENSP00000336945.4

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7170 AN: 152106 Hom.: 260 Cov.: 31

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.0703

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0396

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0675

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0616 AC: 15439 AN: 250822 AF XY: 0.0596

Gnomad AFR exome AF: 0.00929

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.0530

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0456

Gnomad NFE exome AF: 0.0666

Gnomad OTH exome AF: 0.0592

GnomAD4 exome AF: 0.0626 AC: 91508 AN: 1460926 Hom.: 3169 Cov.: 31 AF XY: 0.0621 AC XY: 45131 AN XY: 726852

African (AFR) AF: 0.00900 AC: 301 AN: 33458

American (AMR) AF: 0.120 AC: 5368 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0548 AC: 1433 AN: 26128

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39696

South Asian (SAS) AF: 0.0482 AC: 4161 AN: 86242

European-Finnish (FIN) AF: 0.0464 AC: 2479 AN: 53416

Middle Eastern (MID) AF: 0.0286 AC: 165 AN: 5766

European-Non Finnish (NFE) AF: 0.0668 AC: 74195 AN: 1111146

Other (OTH) AF: 0.0563 AC: 3399 AN: 60360

GnomAD4 genome AF: 0.0472 AC: 7178 AN: 152224 Hom.: 261 Cov.: 31 AF XY: 0.0457 AC XY: 3399 AN XY: 74440

African (AFR) AF: 0.0118 AC: 489 AN: 41528

American (AMR) AF: 0.0707 AC: 1081 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.0398 AC: 192 AN: 4820

European-Finnish (FIN) AF: 0.0402 AC: 426 AN: 10608

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0675 AC: 4589 AN: 68018

Other (OTH) AF: 0.0407 AC: 86 AN: 2112

Alfa AF: 0.0591 Hom.: 725

Bravo AF: 0.0485

TwinsUK AF: 0.0666 AC: 247

ALSPAC AF: 0.0651 AC: 251

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.0733 AC: 630

ExAC AF: 0.0592 AC: 7182

Asia WGS AF: 0.0190 AC: 68 AN: 3478

EpiCase AF: 0.0668

EpiControl AF: 0.0640

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		5.1
ClinPred		0.025	T
GERP RS		4.2
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2425068; hg19: chr20-34214723; COSMIC: COSV58291269; COSMIC: COSV58291269;