chr19-46838570-G-A

Position:

• chr19-46838570-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004069.6(AP2S1):​c.328-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00979 in 1,613,108 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (14 hom., cov: 32)
  • Exomes 𝑓: 0.010 (91 hom.)
• Consequence: AP2S1 NM_004069.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.28

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-46838570-G-A is Benign according to our data. Variant chr19-46838570-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1208917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1194 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2S1	NM_004069.6	c.328-22C>T		intron_variant		ENST00000263270.11	NP_004060.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP2S1	ENST00000263270.11	c.328-22C>T		intron_variant		1	NM_004069.6	ENSP00000263270	P4

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1193 AN: 152222 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00798 AC: 2004 AN: 251066 Hom.: 14 AF XY: 0.00833 AC XY: 1130 AN XY: 135696

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00637

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00666

Gnomad FIN exome AF: 0.00527

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00866

GnomAD4 exome AF: 0.00999 AC: 14591 AN: 1460768 Hom.: 91 Cov.: 30 AF XY: 0.0101 AC XY: 7305 AN XY: 726744

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00689

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00634

Gnomad4 FIN exome AF: 0.00483

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.00784 AC: 1194 AN: 152340 Hom.: 14 Cov.: 32 AF XY: 0.00698 AC XY: 520 AN XY: 74492

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00724

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0100 Hom.: 4

Bravo AF: 0.00826

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.021
DANN	Benign	0.83

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: rs45527038; hg19: chr19-47341827;