chr8-67506879-G-A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_020361.5(CPA6):​c.544C>T​(p.Arg182*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CPA6
NM_020361.5 stop_gained

Scores

2
3
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.77

Publications

5 publications found
Variant links:
Genes affected
CPA6 (HGNC:17245): (carboxypeptidase A6) The gene encodes a member of the peptidase M14 family of metallocarboxypeptidases. The encoded preproprotein is proteolytically processed to generate the mature enzyme, which catalyzes the release of large hydrophobic C-terminal amino acids. This enzyme has functions ranging from digestion of food to selective biosynthesis of neuroendocrine peptides. Mutations in this gene may be linked to epilepsy and febrile seizures, and a translocation t(6;8)(q26;q13) involving this gene has been associated with Duane retraction syndrome. [provided by RefSeq, May 2016]
CPA6 Gene-Disease associations (from GenCC):
  • benign familial mesial temporal lobe epilepsy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial mesial temporal lobe epilepsy with febrile seizures
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial temporal lobe epilepsy 5
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • febrile seizures, familial, 11
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
  • epilepsy
    Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 8-67506879-G-A is Pathogenic according to our data. Variant chr8-67506879-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CPA6NM_020361.5 linkc.544C>T p.Arg182* stop_gained Exon 6 of 11 ENST00000297770.10 NP_065094.3 Q8N4T0-1
CPA6NM_001440615.1 linkc.544C>T p.Arg182* stop_gained Exon 6 of 7 NP_001427544.1
CPA6XM_017013646.2 linkc.100C>T p.Arg34* stop_gained Exon 6 of 11 XP_016869135.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CPA6ENST00000297770.10 linkc.544C>T p.Arg182* stop_gained Exon 6 of 11 1 NM_020361.5 ENSP00000297770.4 Q8N4T0-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
251026
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1460380
Hom.:
0
Cov.:
29
AF XY:
0.00000963
AC XY:
7
AN XY:
726570
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33426
American (AMR)
AF:
0.0000224
AC:
1
AN:
44650
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26100
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39678
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86208
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.0000117
AC:
13
AN:
1110822
Other (OTH)
AF:
0.00
AC:
0
AN:
60338
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.439
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000329
AC:
5
AN:
152126
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74296
show subpopulations
African (AFR)
AF:
0.0000966
AC:
4
AN:
41426
American (AMR)
AF:
0.00
AC:
0
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000338
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Dec 01, 2016
CeGaT Center for Human Genetics Tuebingen
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Benign
0.68
D
PhyloP100
2.8
Vest4
0.37
GERP RS
2.8
Mutation Taster
=11/189
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs773734224; hg19: chr8-68419114; COSMIC: COSV52728383; API