rs1503363

Variant names:

• chr8-67494469-G-A
• rs1503363
• NM_020361.5:c.637-9680C>T

Variant summary

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

The NM_020361.5(CPA6):​c.637-9680C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 151,950 control chromosomes in the GnomAD database, including 21,595 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 0.49 (21595 hom., cov: 31)
• Consequence: CPA6 NM_020361.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.132
• Publications: 2 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA6	NM_020361.5	c.637-9680C>T		intron_variant	Intron 6 of 10	ENST00000297770.10	NP_065094.3
CPA6	XM_017013646.2	c.193-9680C>T		intron_variant	Intron 6 of 10		XP_016869135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPA6	ENST00000297770.10	c.637-9680C>T		intron_variant	Intron 6 of 10	1	NM_020361.5	ENSP00000297770.4
CPA6	ENST00000479862.6	n.*233-9680C>T		intron_variant	Intron 5 of 7	1		ENSP00000419016.2
CPA6	ENST00000518549.1	n.851-9680C>T		intron_variant	Intron 6 of 7	1
CPA6	ENST00000638254.1	n.*233-9680C>T		intron_variant	Intron 5 of 9	5		ENSP00000491129.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74848 AN: 151832 Hom.: 21544 Cov.: 31

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.477

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

GnomAD4 genome AF: 0.493 AC: 74941 AN: 151950 Hom.: 21595 Cov.: 31 AF XY: 0.488 AC XY: 36247 AN XY: 74256

African (AFR) AF: 0.821 AC: 34042 AN: 41454

American (AMR) AF: 0.383 AC: 5843 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1370 AN: 3468

East Asian (EAS) AF: 0.381 AC: 1966 AN: 5166

South Asian (SAS) AF: 0.353 AC: 1699 AN: 4818

European-Finnish (FIN) AF: 0.365 AC: 3841 AN: 10524

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24672 AN: 67952

Other (OTH) AF: 0.470 AC: 994 AN: 2114

Alfa AF: 0.437 Hom.: 2774

Bravo AF: 0.514

Asia WGS AF: 0.345 AC: 1198 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.56
DANN	Benign	0.54
PhyloP100		0.13
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: rs1503363; hg19: chr8-68406704; COSMIC: COSV52735155;