rs397514499

Positions:

• chr19-46846102-C-A
• chr19-46846102-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004069.6(AP2S1):​c.44G>T​(p.Arg15Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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. R15C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AP2S1 NM_004069.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.23

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-46846103-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AP2S1. . Gene score misZ 2.8609 (greater than the threshold 3.09). Trascript score misZ 3.5154 (greater than threshold 3.09). GenCC has associacion of gene with familial hypocalciuric hypercalcemia 3, autism spectrum disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 19-46846102-C-A is Pathogenic according to our data. Variant chr19-46846102-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 39425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2S1	NM_004069.6	c.44G>T	p.Arg15Leu	missense_variant	2/5	ENST00000263270.11	NP_004060.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP2S1	ENST00000263270.11	c.44G>T	p.Arg15Leu	missense_variant	2/5	1	NM_004069.6	ENSP00000263270	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypocalciuric hypercalcemia 3 Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	May 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute	Mar 08, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 15 of the AP2S1 protein (p.Arg15Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypocalciuric hypercalcemia type 3 (PMID: 23222959, 24081735, 24731014, 26082470, 27913609). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39425). 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). This variant disrupts the p.Arg15 amino acid residue in AP2S1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23222959, 24731014, 26082470, 27050234). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2024	Published functional studies demonstrate this variant disrupts extracellular-calcium homeostasis with a dominant-negative effect of the mutant protein on calcium response (PMID: 26082470, 23222959); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27050234, 25993639, 24731014, 23222959, 27913609, 26082470, 28176280, 24081735, 31391146, 31672324, 32430905, 35586626) -

AP2S1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2024

The AP2S1 c.44G>T variant is predicted to result in the amino acid substitution p.Arg15Leu. This variant has been reported to be pathogenic for familial hypocalciuric hypercalcemia (FHH) (Nesbit et al. 2013. PubMed ID: 23222959; Hendy et al. 2014. PubMed ID: 24731014; Hannan et al. 2015. PubMed ID: 26082470; Mariathasan et al. 2020. PubMed ID: 32430905). Nesbit et al. found three different amino acid changes at the p.Arg15 codon (p.Arg15Cys, p.Arg15His and p.Arg15Leu) in FHH patients who were negative for CASR defects. These alterations at the p.Arg15 codon resulted in decreased sensitivity of CaSR-expressing cells to extracellular calcium, reduced CaSR endocytosis, and decreased intracellular signaling. Of note, cinacalcet-mediated allosteric modulation of the calcium-sensing receptor has been recently demonstrated to be able to correct the loss of function of AP2S1 alterations at the p.Arg15 codon (Howles et al. 2016.PubMed ID: 27276582). In summary, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T;T;D;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	4.1	.;.;.;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.1	D;.;.;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.99, 1.0	.;.;.;D;D
Vest4		0.77
MutPred		0.83		Loss of MoRF binding (P = 0.0211);.;.;Loss of MoRF binding (P = 0.0211);Loss of MoRF binding (P = 0.0211);
MVP		0.74
MPC		2.6
ClinPred		1.0	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

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: rs397514499; hg19: chr19-47349359;