20-35626801-T-C

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 NM_001198863.2(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 NM_001198863.2 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.13

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 0.1452514 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPNE1	NM_152925.3	c.1239A>G	p.Gln413Gln	splice_region_variant, synonymous_variant	Exon 15 of 16	ENST00000397443.7	NP_690902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPNE1	ENST00000397443.7	c.1239A>G	p.Gln413Gln	splice_region_variant, synonymous_variant	Exon 15 of 16	5	NM_152925.3	ENSP00000380585.1
CPNE1	ENST00000437340.5	c.1237-1A>G		splice_acceptor_variant, intron_variant	Intron 14 of 15	1		ENSP00000415597.1

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

Gnomad4 AFR exome AF: 0.00900 AC: 301 AN: 33458

Gnomad4 AMR exome AF: 0.120 AC: 5368 AN: 44714

Gnomad4 ASJ exome AF: 0.0548 AC: 1433 AN: 26128

Gnomad4 EAS exome AF: 0.000176 AC: 7 AN: 39696

Gnomad4 SAS exome AF: 0.0482 AC: 4161 AN: 86242

Gnomad4 FIN exome AF: 0.0464 AC: 2479 AN: 53416

Gnomad4 NFE exome AF: 0.0668 AC: 74195 AN: 1111146

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.0118 AC: 0.0117752 AN: 0.0117752

Gnomad4 AMR AF: 0.0707 AC: 0.0707461 AN: 0.0707461

Gnomad4 ASJ AF: 0.0611 AC: 0.0610599 AN: 0.0610599

Gnomad4 EAS AF: 0.00154 AC: 0.00154381 AN: 0.00154381

Gnomad4 SAS AF: 0.0398 AC: 0.039834 AN: 0.039834

Gnomad4 FIN AF: 0.0402 AC: 0.0401584 AN: 0.0401584

Gnomad4 NFE AF: 0.0675 AC: 0.0674674 AN: 0.0674674

Gnomad4 OTH AF: 0.0407 AC: 0.0407197 AN: 0.0407197

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 v4.3

Name	Calibrated prediction	Score	Prediction
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
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

Publications

LitVar

Other links and lift over

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