rs1503369

Variant names:

• chr8-67509763-T-C
• rs1503369
• NM_020361.5:c.433-145A>G

Variant summary

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

The NM_020361.5(CPA6):​c.433-145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 465,930 control chromosomes in the GnomAD database, including 39,952 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 0.46 (17656 hom., cov: 32)
  • Exomes 𝑓: 0.36 (22296 hom.)
• Consequence: CPA6 NM_020361.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.551
• Publications: 1 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA6	NM_020361.5	c.433-145A>G		intron_variant	Intron 4 of 10	ENST00000297770.10	NP_065094.3
CPA6	NM_001440615.1	c.433-145A>G		intron_variant	Intron 4 of 6		NP_001427544.1
CPA6	XM_017013646.2	c.-12-145A>G		intron_variant	Intron 4 of 10		XP_016869135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPA6	ENST00000297770.10	c.433-145A>G		intron_variant	Intron 4 of 10	1	NM_020361.5	ENSP00000297770.4
CPA6	ENST00000479862.6	n.*29-145A>G		intron_variant	Intron 3 of 7	1		ENSP00000419016.2
CPA6	ENST00000518549.1	n.647-145A>G		intron_variant	Intron 4 of 7	1
CPA6	ENST00000638254.1	n.*29-145A>G		intron_variant	Intron 3 of 9	5		ENSP00000491129.1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69757 AN: 151922 Hom.: 17619 Cov.: 32

Gnomad AFR AF: 0.698

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.454

GnomAD4 exome AF: 0.364 AC: 114396 AN: 313890 Hom.: 22296 AF XY: 0.363 AC XY: 58980 AN XY: 162320

African (AFR) AF: 0.694 AC: 5511 AN: 7944

American (AMR) AF: 0.358 AC: 3473 AN: 9698

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 3991 AN: 10400

East Asian (EAS) AF: 0.314 AC: 7617 AN: 24296

South Asian (SAS) AF: 0.345 AC: 5349 AN: 15490

European-Finnish (FIN) AF: 0.338 AC: 11099 AN: 32860

Middle Eastern (MID) AF: 0.432 AC: 637 AN: 1474

European-Non Finnish (NFE) AF: 0.359 AC: 69147 AN: 192342

Other (OTH) AF: 0.391 AC: 7572 AN: 19386

GnomAD4 genome AF: 0.459 AC: 69835 AN: 152040 Hom.: 17656 Cov.: 32 AF XY: 0.455 AC XY: 33804 AN XY: 74310

African (AFR) AF: 0.699 AC: 29013 AN: 41510

American (AMR) AF: 0.372 AC: 5673 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1356 AN: 3470

East Asian (EAS) AF: 0.382 AC: 1979 AN: 5176

South Asian (SAS) AF: 0.353 AC: 1703 AN: 4818

European-Finnish (FIN) AF: 0.365 AC: 3856 AN: 10560

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.365 AC: 24765 AN: 67938

Other (OTH) AF: 0.448 AC: 945 AN: 2108

Alfa AF: 0.413 Hom.: 1846

Bravo AF: 0.476

Asia WGS AF: 0.334 AC: 1153 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.9
DANN	Benign	0.47
PhyloP100		-0.55
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: rs1503369; hg19: chr8-68421998;