rs138798669

Positions:

chr8-67484792-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The ENST00000297770.10(CPA6):c.637-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,532,088 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

CPA6
ENST00000297770.10 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00007036

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.57

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 8-67484792-A-G is Benign according to our data. Variant chr8-67484792-A-G is described in ClinVar as [Benign]. Clinvar id is 472762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-67484792-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
CPA6	NM_020361.5 linkuse as main transcript	c.637-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000297770.10	NP_065094.3
ARFGEF1-DT	NR_136224.1 linkuse as main transcript	n.694-6173A>G	intron_variant, non_coding_transcript_variant
CPA6	XM_017013646.2 linkuse as main transcript	c.193-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		XP_016869135.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
CPA6	ENST00000297770.10 linkuse as main transcript	c.637-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_020361.5	ENSP00000297770	P1	Q8N4T0-1
CPA6	ENST00000479862.6 linkuse as main transcript	c.*233-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	1		ENSP00000419016		Q8N4T0-3
CPA6	ENST00000518549.1 linkuse as main transcript	n.851-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	1
CPA6	ENST00000638254.1 linkuse as main transcript	c.*233-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	5		ENSP00000491129		Q8N4T0-3

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

422

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00972

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.00287

GnomAD3 exomes

AF:

0.000780

AC:

188

AN:

240878

Hom.:

AF XY:

0.000646

AC XY:

AN XY:

130112

show subpopulations

Gnomad AFR exome

AF:

0.0107

Gnomad AMR exome

AF:

0.000474

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:

0.00000903

Gnomad OTH exome

AF:

0.000512

GnomAD4 exome

AF:

0.000259

AC:

358

AN:

1379740

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

146

AN XY:

689718

show subpopulations

Gnomad4 AFR exome

AF:

0.00976

Gnomad4 AMR exome

AF:

0.000401

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000288

Gnomad4 OTH exome

AF:

0.000538

GnomAD4 genome

AF:

0.00277

AC:

422

AN:

152348

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

218

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00969

Gnomad4 AMR

AF:

0.000850

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:

0.00284

Alfa

AF:

0.00140

Hom.:

Bravo

AF:

0.00348

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 10, 2020

- -

Febrile seizures, familial, 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000070

dbscSNV1_RF

Benign

0.0060

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