rs147046973
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_020361.5(CPA6):c.916G>A(p.Val306Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,614,104 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00074 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )
Consequence
CPA6
NM_020361.5 missense
NM_020361.5 missense
Scores
1
4
14
Clinical Significance
Conservation
PhyloP100: 7.54
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.013920099).
BP6
?
Variant 8-67434163-C-T is Benign according to our data. Variant chr8-67434163-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472765.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPA6 | NM_020361.5 | c.916G>A | p.Val306Ile | missense_variant | 9/11 | ENST00000297770.10 | |
ARFGEF1-DT | NR_136224.1 | n.470-8047C>T | intron_variant, non_coding_transcript_variant | ||||
CPA6 | XM_017013646.2 | c.472G>A | p.Val158Ile | missense_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPA6 | ENST00000297770.10 | c.916G>A | p.Val306Ile | missense_variant | 9/11 | 1 | NM_020361.5 | P1 | |
CPA6 | ENST00000479862.6 | c.*435-11472G>A | intron_variant, NMD_transcript_variant | 1 | |||||
CPA6 | ENST00000639116.1 | n.436G>A | non_coding_transcript_exon_variant | 2/4 | 5 | ||||
CPA6 | ENST00000638254.1 | c.*512G>A | 3_prime_UTR_variant, NMD_transcript_variant | 8/10 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000723 AC: 110AN: 152200Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000207 AC: 52AN: 251484Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135916
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GnomAD4 exome AF: 0.0000753 AC: 110AN: 1461786Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49AN XY: 727194
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GnomAD4 genome ? AF: 0.000735 AC: 112AN: 152318Hom.: 1 Cov.: 32 AF XY: 0.000685 AC XY: 51AN XY: 74484
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial temporal lobe epilepsy 5;C3280734:Febrile seizures, familial, 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Feb 03, 2022 | CPA6 NM_020361.4 p.Val306Ile exon 9 (c.916G>A):This variant has not been reported in the literature in individuals with disease but is present in 0.2% (104/41450) of African alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/8-67434163-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:472765). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. In vitro functional studies predict that this variant will impact the protein (Sapio 2012 PMID:23105115). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Febrile seizures, familial, 11 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at