rs766728291

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_020361.5(CPA6):c.534+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000055 in 1,417,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

CPA6
NM_020361.5 splice_region, intron

Scores

Splicing: ADA: 0.9965

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.90

Publications

0 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 Gene-Disease associations (from GenCC):

benign familial mesial temporal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial mesial temporal lobe epilepsy with febrile seizures
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial temporal lobe epilepsy 5
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
febrile seizures, familial, 11
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
epilepsy
Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

CPA6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CPA6	NM_020361.5 link	c.534+4A>G	splice_region_variant, intron_variant	Intron 5 of 10	ENST00000297770.10	NP_065094.3	Q8N4T0-1
CPA6	NM_001440615.1 link	c.534+4A>G	splice_region_variant, intron_variant	Intron 5 of 6		NP_001427544.1
CPA6	XM_017013646.2 link	c.90+4A>G	splice_region_variant, intron_variant	Intron 5 of 10		XP_016869135.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPA6	ENST00000297770.10 link	c.534+4A>G	splice_region_variant, intron_variant	Intron 5 of 10	1	NM_020361.5	ENSP00000297770.4	Q8N4T0-1
CPA6	ENST00000479862.6 link	n.*130+4A>G	splice_region_variant, intron_variant	Intron 4 of 7	1		ENSP00000419016.2	Q8N4T0-3
CPA6	ENST00000518549.1 link	n.748+4A>G	splice_region_variant, intron_variant	Intron 5 of 7	1
CPA6	ENST00000638254.1 link	n.*130+4A>G	splice_region_variant, intron_variant	Intron 4 of 9	5		ENSP00000491129.1	Q8N4T0-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000255

AC:

AN:

235698

AF XY:

0.0000393

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000547

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000593

AC:

AN:

1265322

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

638764

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29102

American (AMR)

AF:

0.00

AC:

AN:

39916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24496

East Asian (EAS)

AF:

0.00

AC:

AN:

38406

South Asian (SAS)

AF:

0.00

AC:

AN:

77612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5286

European-Non Finnish (NFE)

AF:

0.0000774

AC:

AN:

943578

Other (OTH)

AF:

0.0000372

AC:

AN:

53826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

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:

0.0000582

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Febrile seizures, familial, 11

Uncertain:1

Feb 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with CPA6-related disease. This variant is present in population databases (rs766728291, ExAC 0.006%). This sequence change falls in intron 5 of the CPA6 gene. It does not directly change the encoded amino acid sequence of the CPA6 protein, but it affects a nucleotide within the consensus splice site of the intron. -

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.54

Position offset: 4

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