19-46838532-T-C

Variant names:

• chr19-46838532-T-C
• NM_004069.6:c.344A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004069.6(AP2S1):​c.344A>G​(p.Asp115Gly) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: AP2S1 NM_004069.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

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.344A>G	p.Asp115Gly	missense	Exon 5 of 5	NP_004060.2	P53680-1
	AP2S1	NM_001301076.3		c.392A>G	p.Asp131Gly	missense	Exon 5 of 5	NP_001288005.1	M0QYZ2
	AP2S1	NM_001301078.3		c.386A>G	p.Asp129Gly	missense	Exon 5 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.344A>G	p.Asp115Gly	missense	Exon 5 of 5	ENSP00000263270.6	P53680-1
	AP2S1	ENST00000597020.5	TSL:1	c.284A>G	p.Asp95Gly	missense	Exon 4 of 4	ENSP00000470235.1	M0QZ21
	AP2S1	ENST00000600964.1	TSL:1	n.98A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.018	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.028	D
Polyphen		0.031	B
Vest4		0.70
MutPred		0.80		Loss of phosphorylation at Y111 (P = 0.2865)
MVP		0.79
MPC		2.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.87
gMVP		1.0
Mutation Taster		=25/75	disease causing

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

Other links and lift over

hg19: chr19-47341789;