Genetic Variant CPNE8:p.Thr250Ala (chr12-38730333-T-C) – 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.748A>G(p.Thr250Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000027 in 1,443,164 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

CPNE8
NM_153634.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.48

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.748A>G	p.Thr250Ala	missense_variant	Exon 11 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.748A>G	p.Thr250Ala	missense_variant	Exon 11 of 20	1	NM_153634.3	ENSP00000329748.5	Q86YQ8-1
CPNE8	ENST00000360449.3 link	c.712A>G	p.Thr238Ala	missense_variant	Exon 11 of 20	2		ENSP00000353633.3	E7ENV7
CPNE8	ENST00000551855.1 link	n.256A>G		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

243818

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000308

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:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000270

AC:

AN:

1443164

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

718880

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000901

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:

0.0000301

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000313

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.748A>G (p.T250A) alteration is located in exon 11 (coding exon 11) of the CPNE8 gene. This alteration results from a A to G substitution at nucleotide position 748, causing the threonine (T) at amino acid position 250 to be replaced by an alanine (A). 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

0.15

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.9

D;D

REVEL

Benign

0.24

Sift

Benign

0.080

T;T

Sift4G

Benign

0.061

T;T

Polyphen

0.75

P;.

Vest4

0.74

MutPred

0.59

Gain of sheet (P = 0.0827);.;

MVP

0.64

MPC

1.1

ClinPred

0.94

GERP RS

4.3

Varity_R

0.38

gMVP

0.66

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over