Genetic Variant CPNE8:p.Arg4His (chr12-38905524-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153634.3(CPNE8):c.11G>A(p.Arg4His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,565,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CPNE8
NM_153634.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

Publications

2 publications found

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:

CPNE8-AS1 (HGNC:53937): (CPNE8 antisense RNA 1)

CPNE8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010912925).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153634.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPNE8	NM_153634.3	MANE Select	c.11G>A	p.Arg4His	missense	Exon 1 of 20	NP_705898.1	Q86YQ8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPNE8	ENST00000331366.10	TSL:1 MANE Select	c.11G>A	p.Arg4His	missense	Exon 1 of 20	ENSP00000329748.5	Q86YQ8-1
CPNE8	ENST00000862791.1		c.11G>A	p.Arg4His	missense	Exon 1 of 20	ENSP00000532850.1
CPNE8	ENST00000360449.3	TSL:2	c.62+1795G>A		intron	N/A	ENSP00000353633.3	E7ENV7

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152202

Hom.:

Cov.:

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:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000693

AC:

AN:

173042

AF XY:

0.0000327

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000902

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000156

AC:

AN:

1413296

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

698444

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32648

American (AMR)

AF:

0.00

AC:

AN:

37166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25310

East Asian (EAS)

AF:

0.000532

AC:

AN:

37582

South Asian (SAS)

AF:

0.00

AC:

AN:

80474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5498

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1087172

Other (OTH)

AF:

0.00

AC:

AN:

58592

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000679

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

Eigen

Benign

-0.023

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.79

M_CAP

Benign

0.0074

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

1.8

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.38

REVEL

Benign

0.056

Sift

Benign

0.036

Sift4G

Benign

0.19

Polyphen

0.47

Vest4

0.25

MVP

0.39

MPC

0.45

ClinPred

0.13

GERP RS

4.7

PromoterAI

0.044

Neutral

(source)

Varity_R

0.17

gMVP

0.28

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over