16-57110783-C-A

Variant names:

• chr16-57110783-C-A
• rs146049240
• NM_152727.6:c.41C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152727.6(CPNE2):​c.41C>A​(p.Ala14Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000716 in 1,613,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00075 (0 hom.)
• Consequence: CPNE2 NM_152727.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.103

Genes affected

CPNE2 (HGNC:2315): (copine 2) Calcium-dependent membrane-binding proteins may regulate molecular events at the interface of the cell membrane and cytoplasm. This gene is one of several genes that encode a calcium-dependent protein containing two N-terminal type II C2 domains and an integrin A domain-like sequence in the C-terminus. Sequence analysis identified multiple alternatively spliced transcript variants but their full-length natures could not be determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020005107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPNE2	NM_152727.6	c.41C>A	p.Ala14Glu	missense_variant	Exon 2 of 16	ENST00000290776.13	NP_689940.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPNE2	ENST00000290776.13	c.41C>A	p.Ala14Glu	missense_variant	Exon 2 of 16	1	NM_152727.6	ENSP00000290776.8
CPNE2	ENST00000535318.6	c.41C>A	p.Ala14Glu	missense_variant	Exon 3 of 17	1		ENSP00000439018.2
CPNE2	ENST00000565874.5	c.41C>A	p.Ala14Glu	missense_variant	Exon 1 of 15	1		ENSP00000456042.1
CPNE2	ENST00000566259.1	c.41C>A	p.Ala14Glu	missense_variant	Exon 2 of 3	3		ENSP00000455883.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152244 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000808

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000289 AC: 72 AN: 249368 Hom.: 0 AF XY: 0.000333 AC XY: 45 AN XY: 135010

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000578

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000750 AC: 1096 AN: 1460912 Hom.: 0 Cov.: 30 AF XY: 0.000765 AC XY: 556 AN XY: 726760

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000959

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152362 Hom.: 0 Cov.: 31 AF XY: 0.000349 AC XY: 26 AN XY: 74510

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000681 Hom.: 0

Bravo AF: 0.000476

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000600

EpiControl AF: 0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41C>A (p.A14E) alteration is located in exon 2 (coding exon 1) of the CPNE2 gene. This alteration results from a C to A substitution at nucleotide position 41, causing the alanine (A) at amino acid position 14 to be replaced by a glutamic acid (E). 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	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.027	T;T;.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.65	.;.;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.020	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.90	L;L;.;L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.62	N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.21	T;T;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.079	B;B;.;B
Vest4		0.56
MVP		0.36
MPC		1.0
ClinPred		0.034	T
GERP RS		0.15
Varity_R		0.072
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs146049240; hg19: chr16-57144695;