8-67624235-A-G

Position:

chr8-67624235-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 links:

CPA6 (HGNC:):

CPA6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 128845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-67624235-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
CPA6	NM_020361.5 linkuse as main transcript	c.133T>C	p.Phe45Leu	missense_variant	2/11	ENST00000297770.10	NP_065094.3	Q8N4T0-1
CPA6	XM_017013647.2 linkuse as main transcript	c.133T>C	p.Phe45Leu	missense_variant	2/7		XP_016869136.1
CPA6	XM_017013646.2 linkuse as main transcript	c.-187T>C		5_prime_UTR_variant	3/11		XP_016869135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CPA6	ENST00000297770.10 linkuse as main transcript	c.133T>C	p.Phe45Leu	missense_variant	2/11	1	NM_020361.5	ENSP00000297770.4	Q8N4T0-1
CPA6	ENST00000479862.6 linkuse as main transcript	n.133T>C		non_coding_transcript_exon_variant	2/8	1		ENSP00000419016.2	Q8N4T0-3
CPA6	ENST00000518549.1 linkuse as main transcript	n.347T>C		non_coding_transcript_exon_variant	2/8	1
CPA6	ENST00000638254.1 linkuse as main transcript	n.133T>C		non_coding_transcript_exon_variant	2/10	5		ENSP00000491129.1	Q8N4T0-3

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

GnomAD3 exomes

AF:

0.229

AC:

56017

AN:

244758

Hom.:

6746

AF XY:

0.228

AC XY:

30095

AN XY:

132262

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 SAS exome

AF:

0.247

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

Gnomad4 AFR exome

AF:

0.309

Gnomad4 AMR exome

AF:

0.223

Gnomad4 ASJ exome

AF:

0.203

Gnomad4 EAS exome

AF:

0.121

Gnomad4 SAS exome

AF:

0.252

Gnomad4 FIN exome

AF:

0.213

Gnomad4 NFE exome

AF:

0.232

Gnomad4 OTH exome

AF:

0.219

GnomAD4 genome

AF:

0.256

AC:

38920

AN:

152092

Hom.:

5181

Cov.:

AF XY:

0.256

AC XY:

19045

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.325

Gnomad4 AMR

AF:

0.244

Gnomad4 ASJ

AF:

0.211

Gnomad4 EAS

AF:

0.111

Gnomad4 SAS

AF:

0.246

Gnomad4 FIN

AF:

0.224

Gnomad4 NFE

AF:

0.239

Gnomad4 OTH

AF:

0.215

Alfa

AF:

0.239

Hom.:

7401

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Febrile seizures, familial, 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Familial temporal lobe epilepsy 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

PrimateAI

Benign

0.44

PROVEAN

Benign

1.4

REVEL

Benign

0.064

Sift

Benign

0.31

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.048

MutPred

0.18

Gain of ubiquitination at K48 (P = 0.0898);

MPC

0.032

ClinPred

0.011

GERP RS

4.5

Varity_R

0.088

gMVP

0.50

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

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