8-67497263-G-T

Variant names:

• chr8-67497263-G-T
• rs6472312
• NM_020361.5:c.636+9524C>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.636+9524C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 151,974 control chromosomes in the GnomAD database, including 18,450 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 0.47 (18450 hom., cov: 31)
• Consequence: CPA6 NM_020361.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.438
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020361.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA6	NM_020361.5	MANE Select	c.636+9524C>A		intron	N/A	NP_065094.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA6	ENST00000297770.10	TSL:1 MANE Select	c.636+9524C>A		intron	N/A	ENSP00000297770.4
	CPA6	ENST00000479862.6	TSL:1	n.*232+9524C>A		intron	N/A	ENSP00000419016.2
	CPA6	ENST00000518549.1	TSL:1	n.850+9524C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70748 AN: 151854 Hom.: 18407 Cov.: 31

Gnomad AFR AF: 0.728

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.466 AC: 70834 AN: 151974 Hom.: 18450 Cov.: 31 AF XY: 0.462 AC XY: 34320 AN XY: 74284

African (AFR) AF: 0.728 AC: 30208 AN: 41468

American (AMR) AF: 0.372 AC: 5674 AN: 15264

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

East Asian (EAS) AF: 0.380 AC: 1957 AN: 5156

South Asian (SAS) AF: 0.352 AC: 1698 AN: 4818

European-Finnish (FIN) AF: 0.365 AC: 3851 AN: 10542

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.362 AC: 24615 AN: 67942

Other (OTH) AF: 0.449 AC: 948 AN: 2112

Alfa AF: 0.298 Hom.: 1080

Bravo AF: 0.482

Asia WGS AF: 0.335 AC: 1162 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.48
DANN	Benign	0.39
PhyloP100		-0.44
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: rs6472312; hg19: chr8-68409498;