rs9643584

Variant names:

• chr8-67628457-C-T
• rs9643584
• NM_020361.5:c.117-4206G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020361.5(CPA6):​c.117-4206G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 152,052 control chromosomes in the GnomAD database, including 5,962 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (5962 hom., cov: 32)
• Consequence: CPA6 NM_020361.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.118
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA6	NM_020361.5	c.117-4206G>A		intron_variant	Intron 1 of 10	ENST00000297770.10	NP_065094.3
CPA6	NM_001440615.1	c.117-4206G>A		intron_variant	Intron 1 of 6		NP_001427544.1
CPA6	XM_017013646.2	c.-203-4206G>A		intron_variant	Intron 2 of 10		XP_016869135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPA6	ENST00000297770.10	c.117-4206G>A		intron_variant	Intron 1 of 10	1	NM_020361.5	ENSP00000297770.4
CPA6	ENST00000479862.6	n.117-4206G>A		intron_variant	Intron 1 of 7	1		ENSP00000419016.2
CPA6	ENST00000518549.1	n.331-4206G>A		intron_variant	Intron 1 of 7	1
CPA6	ENST00000638254.1	n.117-4206G>A		intron_variant	Intron 1 of 9	5		ENSP00000491129.1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41945 AN: 151934 Hom.: 5959 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.239

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.276 AC: 41969 AN: 152052 Hom.: 5962 Cov.: 32 AF XY: 0.278 AC XY: 20626 AN XY: 74320

African (AFR) AF: 0.336 AC: 13918 AN: 41450

American (AMR) AF: 0.258 AC: 3943 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 969 AN: 3470

East Asian (EAS) AF: 0.114 AC: 589 AN: 5170

South Asian (SAS) AF: 0.311 AC: 1500 AN: 4828

European-Finnish (FIN) AF: 0.264 AC: 2789 AN: 10554

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.258 AC: 17572 AN: 67998

Other (OTH) AF: 0.236 AC: 497 AN: 2102

Alfa AF: 0.265 Hom.: 14612

Bravo AF: 0.274

Asia WGS AF: 0.198 AC: 692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.1
DANN	Benign	0.55
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9643584; hg19: chr8-68540692;