rs17343819

Positions:

• chr8-67484680-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020361.5(CPA6):​c.746A>G​(p.Asn249Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,514,380 control chromosomes in the GnomAD database, including 14,764 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1133 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13631 hom.)
• Consequence: CPA6 NM_020361.5 missense, splice_region
• Scores: Splicing: ADA: 0.1073
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.10

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019486845).
• BP6: Variant 8-67484680-T-C is Benign according to our data. Variant chr8-67484680-T-C is described in ClinVar as [Benign]. Clinvar id is 128847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPA6	NM_020361.5	c.746A>G	p.Asn249Ser	missense_variant, splice_region_variant	7/11	ENST00000297770.10
ARFGEF1-DT	NR_136224.1	n.694-6285T>C		intron_variant, non_coding_transcript_variant
CPA6	XM_017013646.2	c.302A>G	p.Asn101Ser	missense_variant, splice_region_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA6	ENST00000297770.10	c.746A>G	p.Asn249Ser	missense_variant, splice_region_variant	7/11	1	NM_020361.5	P1
CPA6	ENST00000518549.1	n.960A>G		splice_region_variant, non_coding_transcript_exon_variant	7/8	1
CPA6	ENST00000479862.6	c.*342A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	6/8	1
CPA6	ENST00000638254.1	c.*342A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	6/10	5

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17099 AN: 152124 Hom.: 1135 Cov.: 32

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0720

Gnomad FIN AF: 0.0707

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.136

GnomAD3 exomes AF: 0.112 AC: 27734 AN: 247030 Hom.: 1906 AF XY: 0.115 AC XY: 15336 AN XY: 133476

Gnomad AFR exome AF: 0.0598

Gnomad AMR exome AF: 0.0911

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.000773

Gnomad SAS exome AF: 0.0827

Gnomad FIN exome AF: 0.0772

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.135 AC: 184404 AN: 1362138 Hom.: 13631 Cov.: 20 AF XY: 0.135 AC XY: 92233 AN XY: 683486

Gnomad4 AFR exome AF: 0.0584

Gnomad4 AMR exome AF: 0.0962

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.000612

Gnomad4 SAS exome AF: 0.0831

Gnomad4 FIN exome AF: 0.0780

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.112 AC: 17092 AN: 152242 Hom.: 1133 Cov.: 32 AF XY: 0.108 AC XY: 8039 AN XY: 74442

Gnomad4 AFR AF: 0.0610

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0727

Gnomad4 FIN AF: 0.0707

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.135

Alfa AF: 0.148 Hom.: 3951

Bravo AF: 0.115

TwinsUK AF: 0.159 AC: 591

ALSPAC AF: 0.149 AC: 576

ESP6500AA AF: 0.0626 AC: 276

ESP6500EA AF: 0.156 AC: 1338

ExAC AF: 0.112 AC: 13560

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2016	- -

Febrile seizures, familial, 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 20, 2017

- -

Familial temporal lobe epilepsy 5 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.48	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.062
Sift	Benign	0.30	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.093
MPC		0.027
ClinPred		0.0025	T
GERP RS		4.1
Varity_R		0.037
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17343819; hg19: chr8-68396915;