rs147046973

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_020361.5(CPA6):c.916G>A(p.Val306Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,614,104 control chromosomes in the GnomAD database, including 1 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 0.00074 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

CPA6
NM_020361.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.54

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:):

ARFGEF1-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013920099).

BP6

Variant 8-67434163-C-T is Benign according to our data. Variant chr8-67434163-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472765.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CPA6	NM_020361.5 linkuse as main transcript	c.916G>A	p.Val306Ile	missense_variant	9/11	ENST00000297770.10
ARFGEF1-DT	NR_136224.1 linkuse as main transcript	n.470-8047C>T		intron_variant, non_coding_transcript_variant
CPA6	XM_017013646.2 linkuse as main transcript	c.472G>A	p.Val158Ile	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA6	ENST00000297770.10 linkuse as main transcript	c.916G>A	p.Val306Ile	missense_variant	9/11	1	NM_020361.5	P1	Q8N4T0-1
CPA6	ENST00000479862.6 linkuse as main transcript	c.*435-11472G>A		intron_variant, NMD_transcript_variant		1			Q8N4T0-3
CPA6	ENST00000639116.1 linkuse as main transcript	n.436G>A		non_coding_transcript_exon_variant	2/4	5
CPA6	ENST00000638254.1 linkuse as main transcript	c.*512G>A		3_prime_UTR_variant, NMD_transcript_variant	8/10	5			Q8N4T0-3

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000207

AC:

AN:

251484

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00301

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000753

AC:

110

AN:

1461786

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00293

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000735

AC:

112

AN:

152318

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00255

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000242

Hom.:

Bravo

AF:

0.000790

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000288

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 03, 2022

CPA6 NM_020361.4 p.Val306Ile exon 9 (c.916G>A):This variant has not been reported in the literature in individuals with disease but is present in 0.2% (104/41450) of African alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/8-67434163-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:472765). 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 predict 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. -

Febrile seizures, familial, 11

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.0083

Eigen

Benign

0.091

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

M_CAP

Benign

0.031

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.26

REVEL

Benign

0.16

Sift

Uncertain

0.0080

Sift4G

Benign

0.11

Polyphen

0.13

Vest4

0.63

MVP

0.19

MPC

0.22

ClinPred

0.096

GERP RS

5.0

Varity_R

0.44

gMVP

0.68

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