rs397514498

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV004175283: 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" and additional evidence is available in ClinVar. 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:13
• Conservation: PhyloP100: 6.96
• Publications: 25 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004175283: 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); SCV001401307: Experimental studies have shown that this missense change affects AP2S1 function (PMID: 23222959, 26082470).; SCV002525371: 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); SCV005361813: 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. PMID:23222959
• 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 VariationId is 39426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 VariationId is 39424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004069.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2S1	NM_004069.6	MANE Select	c.43C>T	p.Arg15Cys	missense	Exon 2 of 5	NP_004060.2	P53680-1
	AP2S1	NM_001301076.3		c.91C>T	p.Arg31Cys	missense	Exon 2 of 5	NP_001288005.1	M0QYZ2
	AP2S1	NM_001301078.3		c.43C>T	p.Arg15Cys	missense	Exon 2 of 5	NP_001288007.1	X6R390

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2S1	ENST00000263270.11	TSL:1 MANE Select	c.43C>T	p.Arg15Cys	missense	Exon 2 of 5	ENSP00000263270.6	P53680-1
	AP2S1	ENST00000597020.5	TSL:1	c.-18C>T		5_prime_UTR	Exon 1 of 4	ENSP00000470235.1	M0QZ21
	AP2S1	ENST00000960448.1		c.43C>T	p.Arg15Cys	missense	Exon 2 of 6	ENSP00000630507.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Familial hypocalciuric hypercalcemia 3 (8)
4	-	-	not provided (4)
1	-	-	AP2S1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		0.74	P
Vest4		0.73
MutPred		0.86		Loss of MoRF binding (P = 0.0089)
MVP		0.70
MPC		2.2
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		0.0012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514498; hg19: chr19-47349360;