rs142597675

chr8-67422581-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020361.5(CPA6):c.1237C>T(p.Leu413Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,614,032 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (4 hom.)
• Consequence: CPA6 NM_020361.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 7.73

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013078779).
• BP6: Variant 8-67422581-G-A is Benign according to our data. Variant chr8-67422581-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPA6	NM_020361.5	c.1237C>T	p.Leu413Phe	missense_variant	11/11	ENST00000297770.10
ARFGEF1-DT	NR_136224.1	n.470-19629G>A		intron_variant, non_coding_transcript_variant
CPA6	XM_017013646.2	c.793C>T	p.Leu265Phe	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA6	ENST00000297770.10	c.1237C>T	p.Leu413Phe	missense_variant	11/11	1	NM_020361.5	P1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 381 AN: 152118 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00872

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000664 AC: 167 AN: 251412 Hom.: 0 AF XY: 0.000427 AC XY: 58 AN XY: 135864

Gnomad AFR exome AF: 0.00892

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000389 AC: 569 AN: 1461796 Hom.: 4 Cov.: 31 AF XY: 0.000353 AC XY: 257 AN XY: 727212

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.00250 AC: 381 AN: 152236 Hom.: 5 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74424

Gnomad4 AFR AF: 0.00872

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000632 Hom.: 0

Bravo AF: 0.00329

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000848 AC: 103

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CPA6 p.Leu413Phe variant was not identified in the literature but was identified in dbSNP (ID: rs142597675), ClinVar (classified as likely benign by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and EGL Genetics) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 240 of 282796 chromosomes (1 homozygous) at a frequency of 0.000849 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 213 of 24962 chromosomes (freq: 0.008533), Other in 3 of 7224 chromosomes (freq: 0.000415), Latino in 13 of 35436 chromosomes (freq: 0.000367), European (non-Finnish) in 9 of 129114 chromosomes (freq: 0.00007) and South Asian in 2 of 30616 chromosomes (freq: 0.000065), but was not observed in the Ashkenazi Jewish, East Asian and European (Finnish) populations. The p.Leu413 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. However a study of CPA6 variants reported in the general population suggests that although leucine and phenylalanine are similar in size, phenylalanine is a little larger and this may displace the hydrodynamic balance of surrounding residues (Sapio_2012_PMID: 23105115). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 02, 2014

- -

Febrile seizures, familial, 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0066	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.52	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.26
Sift	Benign	0.14	T
Sift4G	Benign	0.70	T
Polyphen		0.26	B
Vest4		0.67
MVP		0.26
MPC		0.24
ClinPred		0.032	T
GERP RS		5.9
Varity_R		0.35
gMVP		0.87

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: rs142597675; hg19: chr8-68334816;