8-67724294-T-C

Variant names:

• chr8-67724294-T-C
• rs2553680
• NM_020361.5:c.116+21720A>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.116+21720A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 152,046 control chromosomes in the GnomAD database, including 34,065 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 0.66 (34065 hom., cov: 31)
• Consequence: CPA6 NM_020361.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00500
• Publications: 4 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 (AMR) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA6	NM_020361.5	c.116+21720A>G		intron_variant	Intron 1 of 10	ENST00000297770.10	NP_065094.3
CPA6	NM_001440615.1	c.116+21720A>G		intron_variant	Intron 1 of 6		NP_001427544.1
CPA6	XM_017013646.2	c.-291+21720A>G		intron_variant	Intron 1 of 10		XP_016869135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPA6	ENST00000297770.10	c.116+21720A>G		intron_variant	Intron 1 of 10	1	NM_020361.5	ENSP00000297770.4
CPA6	ENST00000479862.6	n.116+21720A>G		intron_variant	Intron 1 of 7	1		ENSP00000419016.2
CPA6	ENST00000518549.1	n.330+21720A>G		intron_variant	Intron 1 of 7	1
CPA6	ENST00000638254.1	n.116+21720A>G		intron_variant	Intron 1 of 9	5		ENSP00000491129.1

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100614 AN: 151928 Hom.: 34048 Cov.: 31

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.674

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

GnomAD4 genome AF: 0.662 AC: 100681 AN: 152046 Hom.: 34065 Cov.: 31 AF XY: 0.665 AC XY: 49438 AN XY: 74326

African (AFR) AF: 0.524 AC: 21725 AN: 41444

American (AMR) AF: 0.728 AC: 11133 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2436 AN: 3464

East Asian (EAS) AF: 0.682 AC: 3519 AN: 5160

South Asian (SAS) AF: 0.607 AC: 2919 AN: 4812

European-Finnish (FIN) AF: 0.771 AC: 8147 AN: 10570

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.715 AC: 48601 AN: 67990

Other (OTH) AF: 0.674 AC: 1424 AN: 2112

Alfa AF: 0.691 Hom.: 25900

Bravo AF: 0.653

Asia WGS AF: 0.624 AC: 2169 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	5.2
DANN	Benign	0.46
PhyloP100		0.0050
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2553680; hg19: chr8-68636529;