8-67422705-C-CA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_020361.5(CPA6):c.1127-15_1127-14insT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,130,506 control chromosomes in the GnomAD database, including 200 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.029 (182 hom., cov: 31)
  • Exomes 𝑓: 0.036 (18 hom.)
• Consequence: CPA6 NM_020361.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.525

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]

ARFGEF1-DT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPA6	NM_020361.5	c.1127-15_1127-14insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000297770.10
ARFGEF1-DT	NR_136224.1	n.470-19494dup		intron_variant, non_coding_transcript_variant
CPA6	XM_017013646.2	c.683-15_683-14insT		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA6	ENST00000297770.10	c.1127-15_1127-14insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_020361.5	P1

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4104 AN: 141106 Hom.: 180 Cov.: 31

Gnomad AFR AF: 0.0956

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000611

Gnomad SAS AF: 0.00470

Gnomad FIN AF: 0.00118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00111

Gnomad OTH AF: 0.0241

GnomAD4 exome AF: 0.0362 AC: 35825 AN: 989352 Hom.: 18 Cov.: 18 AF XY: 0.0357 AC XY: 17476 AN XY: 489984

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0403

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.0241

Gnomad4 SAS exome AF: 0.0478

Gnomad4 FIN exome AF: 0.0269

Gnomad4 NFE exome AF: 0.0331

Gnomad4 OTH exome AF: 0.0408

GnomAD4 genome AF: 0.0291 AC: 4112 AN: 141154 Hom.: 182 Cov.: 31 AF XY: 0.0280 AC XY: 1915 AN XY: 68334

Gnomad4 AFR AF: 0.0957

Gnomad4 AMR AF: 0.0168

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000612

Gnomad4 SAS AF: 0.00450

Gnomad4 FIN AF: 0.00118

Gnomad4 NFE AF: 0.00111

Gnomad4 OTH AF: 0.0240

Bravo AF: 0.0309

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial temporal lobe epilepsy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs60236534; hg19: chr8-68334940;