12-38762188-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153634.3(CPNE8):​c.604G>A​(p.Val202Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000493 in 1,603,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V202D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

CPNE8
NM_153634.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.25
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12010643).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CPNE8NM_153634.3 linkc.604G>A p.Val202Ile missense_variant Exon 9 of 20 ENST00000331366.10 NP_705898.1 Q86YQ8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CPNE8ENST00000331366.10 linkc.604G>A p.Val202Ile missense_variant Exon 9 of 20 1 NM_153634.3 ENSP00000329748.5 Q86YQ8-1
CPNE8ENST00000360449.3 linkc.568G>A p.Val190Ile missense_variant Exon 9 of 20 2 ENSP00000353633.3 E7ENV7
CPNE8ENST00000551855.1 linkn.112G>A non_coding_transcript_exon_variant Exon 2 of 5 3

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000611
AC:
15
AN:
245616
Hom.:
0
AF XY:
0.0000376
AC XY:
5
AN XY:
132916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000610
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000116
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000448
AC:
65
AN:
1451136
Hom.:
0
Cov.:
27
AF XY:
0.0000485
AC XY:
35
AN XY:
721992
show subpopulations
Gnomad4 AFR exome
AF:
0.0000302
Gnomad4 AMR exome
AF:
0.0000229
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000118
Gnomad4 FIN exome
AF:
0.0000377
Gnomad4 NFE exome
AF:
0.0000515
Gnomad4 OTH exome
AF:
0.0000500
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152258
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000138
Hom.:
0
Bravo
AF:
0.0000604
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000659
AC:
8
Asia WGS
AF:
0.000289
AC:
1
AN:
3474

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 22, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.604G>A (p.V202I) alteration is located in exon 9 (coding exon 9) of the CPNE8 gene. This alteration results from a G to A substitution at nucleotide position 604, causing the valine (V) at amino acid position 202 to be replaced by an isoleucine (I). 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
0.068
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
21
DANN
Benign
0.76
DEOGEN2
Benign
0.047
T;.
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.84
T;T
M_CAP
Benign
0.0052
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.21
N;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
0.080
N;N
REVEL
Benign
0.096
Sift
Benign
0.81
T;T
Sift4G
Benign
0.86
T;T
Polyphen
0.0
B;.
Vest4
0.26
MVP
0.29
MPC
0.30
ClinPred
0.091
T
GERP RS
3.9
Varity_R
0.033
gMVP
0.12

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143752382; hg19: chr12-39155990; API