8-67422176-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020361.5(CPA6):c.*328A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 208,222 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (86 hom., cov: 32)
  • Exomes 𝑓: 0.029 (39 hom.)
• Consequence: CPA6 NM_020361.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.74

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-67422176-T-C is Benign according to our data. Variant chr8-67422176-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 363596.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-67422176-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0281 (4280/152290) while in subpopulation NFE AF= 0.043 (2927/68028). AF 95% confidence interval is 0.0417. There are 86 homozygotes in gnomad4. There are 1941 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 86 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPA6	NM_020361.5	c.*328A>G		3_prime_UTR_variant	11/11	ENST00000297770.10
ARFGEF1-DT	NR_136224.1	n.470-20034T>C		intron_variant, non_coding_transcript_variant
CPA6	XM_017013646.2	c.*328A>G		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA6	ENST00000297770.10	c.*328A>G		3_prime_UTR_variant	11/11	1	NM_020361.5	P1
CPA6	ENST00000479862.6	c.*950A>G		3_prime_UTR_variant, NMD_transcript_variant	8/8	1
CPA6	ENST00000639508.1	n.615A>G		non_coding_transcript_exon_variant	3/3	5
CPA6	ENST00000638254.1	c.*1238A>G		3_prime_UTR_variant, NMD_transcript_variant	10/10	5

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4279 AN: 152172 Hom.: 86 Cov.: 32

Gnomad AFR AF: 0.00664

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0430

Gnomad OTH AF: 0.0344

GnomAD4 exome AF: 0.0292 AC: 1634 AN: 55932 Hom.: 39 Cov.: 0 AF XY: 0.0288 AC XY: 820 AN XY: 28448

Gnomad4 AFR exome AF: 0.00665

Gnomad4 AMR exome AF: 0.0213

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00637

Gnomad4 FIN exome AF: 0.0202

Gnomad4 NFE exome AF: 0.0368

Gnomad4 OTH exome AF: 0.0296

GnomAD4 genome AF: 0.0281 AC: 4280 AN: 152290 Hom.: 86 Cov.: 32 AF XY: 0.0261 AC XY: 1941 AN XY: 74458

Gnomad4 AFR AF: 0.00664

Gnomad4 AMR AF: 0.0283

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0281

Gnomad4 NFE AF: 0.0430

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0395 Hom.: 129

Bravo AF: 0.0278

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial temporal lobe epilepsy 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.045
Dann	Benign	0.45

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: rs3395; hg19: chr8-68334411;