rs142218524

Variant names:

• chr19-46838160-C-T
• rs142218524
• ENST00000601498.5:c.*287G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000601498.5(AP2S1):​c.*287G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 436,174 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (28 hom., cov: 32)
  • Exomes 𝑓: 0.019 (75 hom.)
• Consequence: AP2S1 ENST00000601498.5 splice_region
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.124
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-46838160-C-T is Benign according to our data. Variant chr19-46838160-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1194555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0149 (2270/152312) while in subpopulation NFE AF = 0.0239 (1625/68026). AF 95% confidence interval is 0.0229. There are 28 homozygotes in GnomAd4. There are 1078 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2270 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000601498.5. 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.*287G>A		downstream_gene	N/A	NP_004060.2	P53680-1
	AP2S1	NM_001301076.3		c.*287G>A		downstream_gene	N/A	NP_001288005.1	M0QYZ2
	AP2S1	NM_001301078.3		c.*287G>A		downstream_gene	N/A	NP_001288007.1	X6R390

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2S1	ENST00000601498.5	TSL:2	c.*287G>A		splice_region	Exon 5 of 5	ENSP00000470176.1	M0QYZ2
	AP2S1	ENST00000599990.5	TSL:2	c.*287G>A		splice_region	Exon 5 of 5	ENSP00000471340.1	M0R0N4
	AP2S1	ENST00000930899.1		c.*287G>A		splice_region	Exon 5 of 5	ENSP00000600958.1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2270 AN: 152194 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00422

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0186 AC: 5285 AN: 283862 Hom.: 75 Cov.: 0 AF XY: 0.0190 AC XY: 2820 AN XY: 148576

African (AFR) AF: 0.00497 AC: 44 AN: 8846

American (AMR) AF: 0.00822 AC: 105 AN: 12774

Ashkenazi Jewish (ASJ) AF: 0.00345 AC: 30 AN: 8686

East Asian (EAS) AF: 0.0000532 AC: 1 AN: 18784

South Asian (SAS) AF: 0.0220 AC: 701 AN: 31836

European-Finnish (FIN) AF: 0.0160 AC: 281 AN: 17592

Middle Eastern (MID) AF: 0.00567 AC: 7 AN: 1234

European-Non Finnish (NFE) AF: 0.0228 AC: 3817 AN: 167606

Other (OTH) AF: 0.0181 AC: 299 AN: 16504

GnomAD4 genome AF: 0.0149 AC: 2270 AN: 152312 Hom.: 28 Cov.: 32 AF XY: 0.0145 AC XY: 1078 AN XY: 74480

African (AFR) AF: 0.00421 AC: 175 AN: 41566

American (AMR) AF: 0.00883 AC: 135 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0221 AC: 107 AN: 4834

European-Finnish (FIN) AF: 0.0167 AC: 177 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0239 AC: 1625 AN: 68026

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.0130 Hom.: 5

Bravo AF: 0.0136

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.6
DANN	Benign	0.67
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142218524; hg19: chr19-47341417;