20-35626767-C-G

Position:

• chr20-35626767-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152925.3(CPNE1):​c.1273G>C​(p.Val425Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CPNE1 NM_152925.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

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]

CPNE1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35880765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPNE1	NM_152925.3	c.1273G>C	p.Val425Leu	missense_variant	15/16	ENST00000397443.7	NP_690902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPNE1	ENST00000397443.7	c.1273G>C	p.Val425Leu	missense_variant	15/16	5	NM_152925.3	ENSP00000380585.1
CPNE1	ENST00000437340.5	c.1270G>C	p.Val424Leu	missense_variant	15/16	1		ENSP00000415597.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

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

Aug 12, 2024

The c.1288G>C (p.V430L) alteration is located in exon 15 (coding exon 15) of the CPNE1 gene. This alteration results from a G to C substitution at nucleotide position 1288, causing the valine (V) at amino acid position 430 to be replaced by a leucine (L). 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	0.40
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T;.;T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.98	L;.;L;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.71	N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.033	D;D;D;D;D
Sift4G	Uncertain	0.060	T;T;T;D;.
Polyphen		0.040	B;P;B;P;P
Vest4		0.29
MutPred		0.80		.;Loss of catalytic residue at V430 (P = 0.0852);.;.;.;
MVP		0.28
MPC		0.32
ClinPred		0.76	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1405701677; hg19: chr20-34214689;