rs61738009

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3BP4_ModerateBS2

The NM_020361.5(CPA6):c.799G>A(p.Gly267Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,614,204 control chromosomes in the GnomAD database, including 9 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 0.0025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 9 hom. )

Consequence

CPA6
NM_020361.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:11B:3

Conservation

PhyloP100: 7.47

Publications

16 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: Likely_benign. The variant received -5 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.13679942).

BS2

High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020361.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA6	NM_020361.5	MANE Select	c.799G>A	p.Gly267Arg	missense	Exon 8 of 11	NP_065094.3
	ARFGEF1-DT	NR_136224.1		n.694-7158C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPA6	ENST00000297770.10	TSL:1 MANE Select	c.799G>A	p.Gly267Arg	missense	Exon 8 of 11	ENSP00000297770.4	Q8N4T0-1
CPA6	ENST00000479862.6	TSL:1	n.*395G>A		non_coding_transcript_exon	Exon 7 of 8	ENSP00000419016.2	Q8N4T0-3
CPA6	ENST00000518549.1	TSL:1	n.1013G>A		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

380

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00321

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00313

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00202

AC:

509

AN:

251470

AF XY:

0.00205

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00311

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00291

AC:

4248

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

2055

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00329

AC:

110

AN:

33478

American (AMR)

AF:

0.00248

AC:

111

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00343

AC:

3813

AN:

1111992

Other (OTH)

AF:

0.00278

AC:

168

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

222

444

666

888

1110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.00249

AC:

380

AN:

152332

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

164

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00320

AC:

133

AN:

41576

American (AMR)

AF:

0.00144

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00313

AC:

213

AN:

68020

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00295

Hom.:

Bravo

AF:

0.00283

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00211

AC:

256

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00462

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Familial temporal lobe epilepsy 5 (3)

Febrile seizures, familial, 11 (2)

not specified (2)

Confusion;C0030252:Palpitations;C0036572:Seizure;C0156404:Irregular menstruation;C0751495:Focal-onset seizure;C4020949:Abnormal emotional state;C5399973:Periventricular heterotopia (1)

CPA6-related disorder (1)

Epilepsy (1)

Familial temporal lobe epilepsy 5;C3280734:Febrile seizures, familial, 11 (1)

Global developmental delay (1)

Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.14

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

4.1

PhyloP100

7.5

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.88

Gain of disorder (P = 0.0488)

MVP

0.86

MPC

0.25

ClinPred

0.16

GERP RS

5.2

Varity_R

0.95

gMVP

0.96

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over