rs397514498

Variant names:

• chr19-46846103-G-A
• rs397514498
• NM_004069.6:c.43C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-46846102-C-T is described in Lovd as [Pathogenic].
• 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 rank	MANE	Protein	UniProt
AP2S1	NM_004069.6	c.43C>T	p.Arg15Cys	missense_variant	Exon 2 of 5	ENST00000263270.11	NP_004060.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP2S1	ENST00000263270.11	c.43C>T	p.Arg15Cys	missense_variant	Exon 2 of 5	1	NM_004069.6	ENSP00000263270.6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypocalciuric hypercalcemia 3 Pathogenic:8

Oct 23, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used: PS3, PS4, PM2, PM5, PP3 -

Jan 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PP2, PP3 -

May 09, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.0.0 dataset. Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.69 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.66 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with BBS10 related disorder (ClinVar ID: VCV000556508 /PMID: 19797195).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 30, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Mar 08, 2024

Molecular Genetics Laboratory, Biobizkaia Health Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:3

Jun 02, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

AP2S1-related disorder Pathogenic:1

Aug 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AP2S1 c.43C>T variant is predicted to result in the amino acid substitution p.Arg15Cys. This variant has been reported to be pathogenic for familial hypocalciuric hypercalcemia (FHH) (Nesbit et al. 2013. PubMed ID: 23222959). 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 are 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). This variant has not been reported in a large population database, and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/39424/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;D;D;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	4.1	.;.;.;H;H
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.8	D;.;.;D;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Uncertain	0.021	D;D;D;D;D
Polyphen		0.74, 0.89	.;.;.;P;P
Vest4		0.73
MutPred		0.86		Loss of MoRF binding (P = 0.0089);.;.;Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);
MVP		0.70
MPC		2.2
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
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: rs397514498; hg19: chr19-47349360;