chr19-46846102-C-T

Variant names:

• chr19-46846102-C-T
• rs397514499
• NM_004069.6:c.44G>A

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.44G>A​(p.Arg15His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AP2S1 NM_004069.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 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 chr19-46846103-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 19-46846102-C-T is Pathogenic according to our data. 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. Variant chr19-46846102-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP2S1	NM_004069.6	c.44G>A	p.Arg15His	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.44G>A	p.Arg15His	missense_variant	Exon 2 of 5	1	NM_004069.6	ENSP00000263270.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial hypocalciuric hypercalcemia 3 Pathogenic:3

Jan 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 15, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2022

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AP2S1 p.Arg15His is one of several pathogenic variants affecting Arg15 and causing familial hypocalciuric hypercalcaemia (FHH) type 3. Functional studies demonstrate decreased sensitivity of p.Arg15His to extracellular calcium and impaired calcium-sensing receptor internalisation (PMID: 23222959, 29420171). -

not provided Pathogenic:2

Aug 31, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a decreased sensitivity to extracellular calcium and reduced CaSR endocytosis (Nesbit et al., 2013; Gorvin CM et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; This variant is associated with the following publications: (PMID: 32047691, 26082470, 27913609, 24731014, 27761240, 27050234, 25993639, 23222959, 29325022, 29420171) -

Jan 19, 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 histidine, which is basic and polar, at codon 15 of the AP2S1 protein (p.Arg15His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with AP2S1-related conditions (PMID: 23222959, 24731014, 26082470, 27050234, 27761240, 29325022). ClinVar contains an entry for this variant (Variation ID: 39426). 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, 29325022, 29420171). 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. -

AP2S1-related disorder Pathogenic:1

Sep 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AP2S1 c.44G>A variant is predicted to result in the amino acid substitution p.Arg15His. This variant has been repeatedly reported in individuals with familial hypocalciuric hypercalcemia (Nesbit et al. 2012. PubMed ID: 23222959; Hendy et al. 2014. PubMed ID: 24731014; Hannan et al. 2015. PubMed ID: 26082470; Aashiq et al 2020. PubMed ID: 32047691). This variant has not been reported in a large population database, indicating this variant is rare. Other amino acid substitutions at this position (p.Arg15Leu, p.Arg15Cys) have also been reported in patients with hypocalciuric hypercalcemia (Hendy GN et al 2014. PubMed ID: 24731014; Nesbit MA et al 2012. PubMed ID: 23222959). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	.;D;D;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	4.1	.;.;.;H;H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D;.;.;D;.
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;.;.;D;D
Vest4		0.72
MutPred		0.90		Loss of MoRF binding (P = 0.0243);.;.;Loss of MoRF binding (P = 0.0243);Loss of MoRF binding (P = 0.0243);
MVP		0.77
MPC		2.1
ClinPred		1.0	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;