Genetic Variant CPNE8:p.Phe63Leu (chr12-38848662-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_153634.3(CPNE8):c.187T>C(p.Phe63Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CPNE8
NM_153634.3 missense, splice_region

Scores

Splicing: ADA: 0.007118

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.99

Variant links:

Genes affected

CPNE8 (HGNC:23498): (copine 8) 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. [provided by RefSeq, Jul 2008]

CPNE8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPNE8	NM_153634.3 link	c.187T>C	p.Phe63Leu	missense_variant, splice_region_variant	Exon 4 of 20	ENST00000331366.10	NP_705898.1	Q86YQ8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPNE8	ENST00000331366.10 link	c.187T>C	p.Phe63Leu	missense_variant, splice_region_variant	Exon 4 of 20	1	NM_153634.3	ENSP00000329748.5	Q86YQ8-1
CPNE8	ENST00000360449.3 link	c.151T>C	p.Phe51Leu	missense_variant, splice_region_variant	Exon 4 of 20	2		ENSP00000353633.3	E7ENV7
CPNE8	ENST00000550863.1 link	c.-297T>C		splice_region_variant	Exon 4 of 8	4		ENSP00000447761.1	F8VZB5
CPNE8	ENST00000550863.1 link	c.-297T>C		5_prime_UTR_variant	Exon 4 of 8	4		ENSP00000447761.1	F8VZB5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1433750

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712664

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.187T>C (p.F63L) alteration is located in exon 4 (coding exon 4) of the CPNE8 gene. This alteration results from a T to C substitution at nucleotide position 187, causing the phenylalanine (F) at amino acid position 63 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

Pathogenic

0.96

BayesDel_addAF

Benign

-0.0019

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.056

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.93

L;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.28

Sift

Benign

0.46

T;T

Sift4G

Benign

0.66

T;T

Polyphen

0.0070

B;.

Vest4

0.79

MutPred

0.35

Loss of sheet (P = 0.0817);.;

MVP

0.40

MPC

0.86

ClinPred

0.98

GERP RS

3.6

Varity_R

0.30

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0071

dbscSNV1_RF

Benign

0.040

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over