8-67434147-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_020361.5(CPA6):c.932G>A(p.Arg311Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00132 in 1,614,020 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 5 hom. )

Consequence

CPA6
NM_020361.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.72

Publications

7 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 links:

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

ARFGEF1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07801762).

BP6

Variant 8-67434147-C-T is Benign according to our data. Variant chr8-67434147-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 363605.

BS2

High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA6	NM_020361.5 link	c.932G>A	p.Arg311Gln	missense_variant	Exon 9 of 11	ENST00000297770.10	NP_065094.3	Q8N4T0-1
CPA6	XM_017013646.2 link	c.488G>A	p.Arg163Gln	missense_variant	Exon 9 of 11		XP_016869135.1
ARFGEF1-DT	NR_136224.1 link	n.470-8063C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPA6	ENST00000297770.10 link	c.932G>A	p.Arg311Gln	missense_variant	Exon 9 of 11	1	NM_020361.5	ENSP00000297770.4		Q8N4T0-1

Frequencies

GnomAD3 genomes

AF:

0.000881

AC:

134

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000958

AC:

241

AN:

251476

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.00136

AC:

1992

AN:

1461768

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

953

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33474

American (AMR)

AF:

0.00103

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00272

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.000661

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000698

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00156

AC:

1735

AN:

1111956

Other (OTH)

AF:

0.00111

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

106

213

319

426

532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.000887

AC:

135

AN:

152252

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41554

American (AMR)

AF:

0.000850

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00104

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

68018

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00116

Hom.:

Bravo

AF:

0.000876

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000972

AC:

118

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 07, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R311Q variant in the CPA6 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R311Q variant is observed in 86/66722 (0.13%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The R311Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, functional studies looking at rare CPA6 variants demonstrated that cells expressing the R311Q variant had reduced enzymatic activity compared to wild type cells (Sapio et al., 2012). We interpret R311Q as a variant of uncertain significance. -

Familial temporal lobe epilepsy 5;C3280734:Febrile seizures, familial, 11

Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals with disease and is present in 0.1% (95/68026) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/8-67434147-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:363605). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. In vitro functional studies suggest that this variant will impact the protein (Sapio 2012 PMID:23105115). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Familial temporal lobe epilepsy 5

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Febrile seizures, familial, 11

Benign:1

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.056

Eigen

Benign

0.0022

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.038

MetaRNN

Benign

0.078

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

PhyloP100

4.7

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.10

Sift

Uncertain

0.015

Sift4G

Uncertain

0.044

Polyphen

0.16

Vest4

0.79

MVP

0.25

MPC

0.23

ClinPred

0.12

GERP RS

5.0

Varity_R

0.46

gMVP

0.77

Mutation Taster

=90/10

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over