rs17343819

Positions:

chr8-67484680-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020361.5(CPA6):c.746A>G(p.Asn249Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,514,380 control chromosomes in the GnomAD database, including 14,764 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1133 hom., cov: 32)

Exomes 𝑓: 0.14 ( 13631 hom. )

Consequence

CPA6
NM_020361.5 missense, splice_region

Scores

Splicing: ADA: 0.1073

Clinical Significance

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

Conservation

PhyloP100: 1.10

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:

ARFGEF1-DT (HGNC:55237): (ARFGEF1 divergent transcript)

ARFGEF1-DT 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=0.0019486845).

BP6

Variant 8-67484680-T-C is Benign according to our data. Variant chr8-67484680-T-C is described in ClinVar as [Benign]. Clinvar id is 128847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPA6	NM_020361.5 link	c.746A>G	p.Asn249Ser	missense_variant, splice_region_variant	7/11	ENST00000297770.10	NP_065094.3	Q8N4T0-1
CPA6	XM_017013646.2 link	c.302A>G	p.Asn101Ser	missense_variant, splice_region_variant	7/11		XP_016869135.1
ARFGEF1-DT	NR_136224.1 link	n.694-6285T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPA6	ENST00000297770.10 link	c.746A>G	p.Asn249Ser	missense_variant, splice_region_variant	7/11	1	NM_020361.5	ENSP00000297770.4		Q8N4T0-1

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

17099

AN:

152124

Hom.:

1135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0611

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0720

Gnomad FIN

AF:

0.0707

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.136

GnomAD3 exomes

AF:

0.112

AC:

27734

AN:

247030

Hom.:

1906

AF XY:

0.115

AC XY:

15336

AN XY:

133476

show subpopulations

Gnomad AFR exome

AF:

0.0598

Gnomad AMR exome

AF:

0.0911

Gnomad ASJ exome

AF:

0.183

Gnomad EAS exome

AF:

0.000773

Gnomad SAS exome

AF:

0.0827

Gnomad FIN exome

AF:

0.0772

Gnomad NFE exome

AF:

0.151

Gnomad OTH exome

AF:

0.142

GnomAD4 exome

AF:

0.135

AC:

184404

AN:

1362138

Hom.:

13631

Cov.:

AF XY:

0.135

AC XY:

92233

AN XY:

683486

show subpopulations

Gnomad4 AFR exome

AF:

0.0584

Gnomad4 AMR exome

AF:

0.0962

Gnomad4 ASJ exome

AF:

0.175

Gnomad4 EAS exome

AF:

0.000612

Gnomad4 SAS exome

AF:

0.0831

Gnomad4 FIN exome

AF:

0.0780

Gnomad4 NFE exome

AF:

0.150

Gnomad4 OTH exome

AF:

0.135

GnomAD4 genome

AF:

0.112

AC:

17092

AN:

152242

Hom.:

1133

Cov.:

AF XY:

0.108

AC XY:

8039

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0610

Gnomad4 AMR

AF:

0.122

Gnomad4 ASJ

AF:

0.178

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0727

Gnomad4 FIN

AF:

0.0707

Gnomad4 NFE

AF:

0.154

Gnomad4 OTH

AF:

0.135

Alfa

AF:

0.148

Hom.:

3951

Bravo

AF:

0.115

TwinsUK

AF:

0.159

AC:

591

ALSPAC

AF:

0.149

AC:

576

ESP6500AA

AF:

0.0626

AC:

276

ESP6500EA

AF:

0.156

AC:

1338

ExAC

AF:

0.112

AC:

13560

Asia WGS

AF:

0.0320

AC:

112

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2016	- -

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

Feb 03, 2025

- -

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

0.063

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0036

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.20

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.48

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.25

REVEL

Benign

0.062

Sift

Benign

0.30

Sift4G

Benign

0.53

Polyphen

0.0010

Vest4

0.093

MPC

0.027

ClinPred

0.0025

GERP RS

4.1

Varity_R

0.037

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.19

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.27

Position offset: -1

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