19-46846102-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.23

Publications

31 publications found

Variant links:

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]

AP2S1 Gene-Disease associations (from GenCC):

familial hypocalciuric hypercalcemia 3
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: G2P
autism spectrum disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

AP2S1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a chain AP-2 complex subunit sigma (size 141) in uniprot entity AP2S1_HUMAN there are 4 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 chr19-46846103-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.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP2S1	NM_004069.6 link	c.44G>A	p.Arg15His	missense_variant	Exon 2 of 5	ENST00000263270.11	NP_004060.2	P53680-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP2S1	ENST00000263270.11 link	c.44G>A	p.Arg15His	missense_variant	Exon 2 of 5	1	NM_004069.6	ENSP00000263270.6		P53680-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypocalciuric hypercalcemia 3

Pathogenic:3

Jul 15, 2022

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

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. -

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) -

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

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

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

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Pathogenic

4.1

.;.;.;H;H

PhyloP100

7.2

PrimateAI

Pathogenic

0.89

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

GERP RS

2.7

PromoterAI

-0.16

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over