8-67624235-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020361.5(CPA6):c.133T>C(p.Phe45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,511,202 control chromosomes in the GnomAD database, including 42,491 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5181 hom., cov: 32)

Exomes 𝑓: 0.23 ( 37310 hom. )

Consequence

CPA6
NM_020361.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.05

Publications

23 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

CPA6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044371784).

BP6

Variant 8-67624235-A-G is Benign according to our data. Variant chr8-67624235-A-G is described in ClinVar as Benign. ClinVar VariationId is 128845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CPA6	NM_020361.5 link	c.133T>C	p.Phe45Leu	missense_variant	Exon 2 of 11	ENST00000297770.10	NP_065094.3
CPA6	NM_001440615.1 link	c.133T>C	p.Phe45Leu	missense_variant	Exon 2 of 7		NP_001427544.1
CPA6	XM_017013646.2 link	c.-187T>C		5_prime_UTR_variant	Exon 3 of 11		XP_016869135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CPA6	ENST00000297770.10 link	c.133T>C	p.Phe45Leu	missense_variant	Exon 2 of 11	1	NM_020361.5	ENSP00000297770.4
CPA6	ENST00000479862.6 link	n.133T>C		non_coding_transcript_exon_variant	Exon 2 of 8	1		ENSP00000419016.2
CPA6	ENST00000518549.1 link	n.347T>C		non_coding_transcript_exon_variant	Exon 2 of 8	1
CPA6	ENST00000638254.1 link	n.133T>C		non_coding_transcript_exon_variant	Exon 2 of 10	5		ENSP00000491129.1

Frequencies

GnomAD3 genomes

AF:

0.256

AC:

38894

AN:

151974

Hom.:

5177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.325

Gnomad AMI

AF:

0.132

Gnomad AMR

AF:

0.244

Gnomad ASJ

AF:

0.211

Gnomad EAS

AF:

0.110

Gnomad SAS

AF:

0.246

Gnomad FIN

AF:

0.224

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.215

GnomAD2 exomes

AF:

0.229

AC:

56017

AN:

244758

AF XY:

0.228

show subpopulations

Gnomad AFR exome

AF:

0.328

Gnomad AMR exome

AF:

0.225

Gnomad ASJ exome

AF:

0.216

Gnomad EAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.217

Gnomad NFE exome

AF:

0.234

Gnomad OTH exome

AF:

0.221

GnomAD4 exome

AF:

0.229

AC:

311803

AN:

1359110

Hom.:

37310

Cov.:

AF XY:

0.230

AC XY:

156726

AN XY:

681000

show subpopulations

African (AFR)

AF:

0.309

AC:

9538

AN:

30906

American (AMR)

AF:

0.223

AC:

9512

AN:

42564

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

5155

AN:

25374

East Asian (EAS)

AF:

0.121

AC:

4728

AN:

39058

South Asian (SAS)

AF:

0.252

AC:

20649

AN:

82090

European-Finnish (FIN)

AF:

0.213

AC:

11278

AN:

52922

Middle Eastern (MID)

AF:

0.228

AC:

1263

AN:

5548

European-Non Finnish (NFE)

AF:

0.232

AC:

237226

AN:

1023700

Other (OTH)

AF:

0.219

AC:

12454

AN:

56948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

9569

19138

28708

38277

47846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7810

15620

23430

31240

39050

<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:

0.256

AC:

38920

AN:

152092

Hom.:

5181

Cov.:

AF XY:

0.256

AC XY:

19045

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.325

AC:

13468

AN:

41454

American (AMR)

AF:

0.244

AC:

3726

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.211

AC:

732

AN:

3468

East Asian (EAS)

AF:

0.111

AC:

572

AN:

5176

South Asian (SAS)

AF:

0.246

AC:

1188

AN:

4828

European-Finnish (FIN)

AF:

0.224

AC:

2364

AN:

10562

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16235

AN:

67994

Other (OTH)

AF:

0.215

AC:

454

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1481

2962

4442

5923

7404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.243

Hom.:

15918

Bravo

AF:

0.257

TwinsUK

AF:

0.256

AC:

948

ALSPAC

AF:

0.242

AC:

932

ESP6500AA

AF:

0.320

AC:

1408

ESP6500EA

AF:

0.236

AC:

2025

ExAC

AF:

0.235

AC:

28590

Asia WGS

AF:

0.178

AC:

620

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jul 07, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Febrile seizures, familial, 11

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial temporal lobe epilepsy 5

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0059

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.2

PhyloP100

3.0

PrimateAI

Benign

0.44

PROVEAN

Benign

1.4

REVEL

Benign

0.064

Sift

Benign

0.31

Sift4G

Benign

0.26

Vest4

0.048

ClinPred

0.011

GERP RS

4.5

Varity_R

0.088

gMVP

0.50

Mutation Taster

=96/4

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over