rs183899632

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_020361.5(CPA6):c.107G>T(p.Arg36Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R36C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CPA6
NM_020361.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.96

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-67746023-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1325821.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.25859475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CPA6	NM_020361.5 linkuse as main transcript	c.107G>T	p.Arg36Leu	missense_variant	1/11	ENST00000297770.10
CPA6	XM_017013647.2 linkuse as main transcript	c.107G>T	p.Arg36Leu	missense_variant	1/7
CPA6	XM_017013646.2 linkuse as main transcript	c.-300G>T		5_prime_UTR_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA6	ENST00000297770.10 linkuse as main transcript	c.107G>T	p.Arg36Leu	missense_variant	1/11	1	NM_020361.5	P1	Q8N4T0-1
CPA6	ENST00000518549.1 linkuse as main transcript	n.321G>T		non_coding_transcript_exon_variant	1/8	1
CPA6	ENST00000479862.6 linkuse as main transcript	c.107G>T	p.Arg36Leu	missense_variant, NMD_transcript_variant	1/8	1			Q8N4T0-3
CPA6	ENST00000638254.1 linkuse as main transcript	c.107G>T	p.Arg36Leu	missense_variant, NMD_transcript_variant	1/10	5			Q8N4T0-3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000558

AC:

AN:

250678

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135482

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1460282

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726476

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Febrile seizures, familial, 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CPA6 protein function. ClinVar contains an entry for this variant (Variation ID: 569405). This variant has not been reported in the literature in individuals affected with CPA6-related conditions. This variant is present in population databases (rs183899632, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 36 of the CPA6 protein (p.Arg36Leu). -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 04, 2021

- -

Seizure

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Aug 14, 2019

The c.107G>T (p.Arg36Leu) variant identified it the CPA6 gene substitutes a moderately conserved Arginine for Leucine at amino acid 36. This variant is found in gnomAD (15 heterozygotes, 0 homozygotes; allele frequency: 5.32e-5) and ExAC (5 heterozygotes, 0 homozygotes; allele frequency: 4.18e-5). In silico algorithms predict this variant to be Neutral (Provean; score: -2.36) and Damaging (SIFT; score: 0.013) to the function of the canonical transcript. This variant is classified in ClinVar as a Varaint of Uncertain Significance (VarID: 569405), and while the c.107G>T (p.Arg36Leu) variant identified in this individual has never been reported in the literature, a different change at the same nucleotide has been reported. A c.107G>A (p.Arg36His) variant in the CPA6 gene was reported in a female with Juvenile Myoclonic Epilepsy [PMID: 25875328]. The reported patient was described with myoclonic seizures, generalized tonic-clonic seizures, and absence seizures that were onset at 16.5 years of age. Functional studies on the p.Arg36His variant demonstrated 50% reduction of the mutant protein in the extracellular matrix [PMID: 25875328]. While a variant at the same nucleotide has been reported in an individual affected with epilepsy, the lack of functional data or additional evidence supporting the pathogenicity for the c.107G>T (p.Arg36Leu) variant identified in this patient results in its report here as a Variant of Uncertain Significance. -

Familial temporal lobe epilepsy 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 30, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.30

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.030

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.82

M_CAP

Benign

0.049

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.97

D;D;D

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.27

Sift

Uncertain

0.013

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.66

MVP

0.63

MPC

0.23

ClinPred

0.40

GERP RS

4.8

Varity_R

0.23

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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