rs397514498
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_004069.6(AP2S1):c.43C>T(p.Arg15Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15H) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 30)
Consequence
AP2S1
NM_004069.6 missense
NM_004069.6 missense
Scores
10
6
1
Clinical Significance
Conservation
PhyloP100: 6.96
Genes affected
AP2S1 (HGNC:565): (adaptor related protein complex 2 subunit sigma 1) One of two major clathrin-associated adaptor complexes, AP-2, is a heterotetramer which is associated with the plasma membrane. This complex is composed of two large chains, a medium chain, and a small chain. This gene encodes the small chain of this complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PM1
?
In a strand (size 5) in uniprot entity AP2S1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_004069.6
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr19-46846102-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, AP2S1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
?
Variant 19-46846103-G-A is Pathogenic according to our data. Variant chr19-46846103-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46846103-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP2S1 | NM_004069.6 | c.43C>T | p.Arg15Cys | missense_variant | 2/5 | ENST00000263270.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP2S1 | ENST00000263270.11 | c.43C>T | p.Arg15Cys | missense_variant | 2/5 | 1 | NM_004069.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial hypocalciuric hypercalcemia 3 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039424, PMID:23222959). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039425,VCV000039426, PMID:23222959,23222959). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.763>=0.6, 3CNET: 0.828>=0.75). A missense variant is a common mechanism associated with Hypocalciuric hypercalcemia, type III. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 30, 2022 | The AP2S1 c.43C>T variant is classified as Pathogenic (PS4, PM2, PM5, PP1, PP3) The AP2S1 c.43C>T variant is a single nucleotide change in exon 2/5 of the AP2S1 gene, which is predicted to change the amino acid arginine at position 15 in the protein to cysteine. The variant has been reported in several probands with a clinical presentation of familial hypocalciuric hypercalcemia (HGMD: CM1212084) (PS4). This variant is absent from population databases (PM2). This variant has been shown to segregate with disease in a 2019 study (Wong et al, 2019; PMID:31723423) (PP1). HEK-CaSR cells expressing Arg15 missense AP2-sigma-2 variants were found to have half-maximal effective concentration (EC50) values that were significantly higher than cells expressing the wild-type AP2-sigma-2 protein (Hannan et al; 2015; PMID:26082470) (PS3_moderate). This variant is a missense change at an amino acid residue where the different missense changes p.Arg15His and p.Arg15Leu has been seen before (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs397514498) and in the HGMD database: CM1212084. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 39424). - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute | Mar 08, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 09, 2017 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2022 | Published functional studies demonstrate this variant impairs the role of AP2S1 in extracellular calcium homeostasis by affected CaSR endocytosis and decreasing sensitivity of cells to extracellular calcium (Nesbit et al., 2013; Hannan et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26082470, 27913609, 27050234, 31672324, 23222959, 33729479, 33168530, 24731014, 31723423) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 15 of the AP2S1 protein (p.Arg15Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia type 3 (PMID: 23222959, 24731014, 26082470, 27050234). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39424). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects AP2S1 function (PMID: 23222959, 26082470). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;D;.
Sift4G
Uncertain
D;D;D;D;D
Polyphen
0.74, 0.89
.;.;.;P;P
Vest4
MutPred
Loss of MoRF binding (P = 0.0089);.;.;Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);
MVP
MPC
2.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at