Variant chr19-46839460-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004069.6(AP2S1):c.267+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,609,702 control chromosomes in the GnomAD database, including 35,509 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5813 hom., cov: 28)

Exomes 𝑓: 0.18 ( 29696 hom. )

Consequence

AP2S1
NM_004069.6 splice_region, intron

Scores

Splicing: ADA: 0.2398

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.19

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 links:

AP2S1 (HGNC:):

AP2S1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 19-46839460-C-T is Benign according to our data. Variant chr19-46839460-C-T is described in ClinVar as [Benign]. Clinvar id is 259227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46839460-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2S1	NM_004069.6 linkuse as main transcript	c.267+5G>A		splice_region_variant, intron_variant		ENST00000263270.11	NP_004060.2	P53680-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP2S1	ENST00000263270.11 linkuse as main transcript	c.267+5G>A		splice_region_variant, intron_variant		1	NM_004069.6	ENSP00000263270.6		P53680-1

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

36762

AN:

150914

Hom.:

5801

Cov.:

show subpopulations

Gnomad AFR

AF:

0.372

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.364

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.505

Gnomad SAS

AF:

0.348

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.238

GnomAD3 exomes

AF:

0.250

AC:

62919

AN:

251404

Hom.:

10596

AF XY:

0.241

AC XY:

32758

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.374

Gnomad AMR exome

AF:

0.466

Gnomad ASJ exome

AF:

0.236

Gnomad EAS exome

AF:

0.506

Gnomad SAS exome

AF:

0.324

Gnomad FIN exome

AF:

0.112

Gnomad NFE exome

AF:

0.136

Gnomad OTH exome

AF:

0.209

GnomAD4 exome

AF:

0.176

AC:

257286

AN:

1458666

Hom.:

29696

Cov.:

AF XY:

0.179

AC XY:

130088

AN XY:

725714

show subpopulations

Gnomad4 AFR exome

AF:

0.378

Gnomad4 AMR exome

AF:

0.449

Gnomad4 ASJ exome

AF:

0.231

Gnomad4 EAS exome

AF:

0.485

Gnomad4 SAS exome

AF:

0.322

Gnomad4 FIN exome

AF:

0.110

Gnomad4 NFE exome

AF:

0.137

Gnomad4 OTH exome

AF:

0.209

GnomAD4 genome

AF:

0.244

AC:

36821

AN:

151036

Hom.:

5813

Cov.:

AF XY:

0.246

AC XY:

18121

AN XY:

73720

show subpopulations

Gnomad4 AFR

AF:

0.372

Gnomad4 AMR

AF:

0.364

Gnomad4 ASJ

AF:

0.230

Gnomad4 EAS

AF:

0.504

Gnomad4 SAS

AF:

0.349

Gnomad4 FIN

AF:

0.103

Gnomad4 NFE

AF:

0.136

Gnomad4 OTH

AF:

0.241

Alfa

AF:

0.175

Hom.:

3523

Bravo

AF:

0.271

Asia WGS

AF:

0.453

AC:

1572

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.267+5G>A in intron 3 of AP2S1: This variant is not expected to have clinical s ignificance because it has been identified in 50.36% (4346/8630) of East Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs312186). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.4

DANN

Benign

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.24

dbscSNV1_RF

Benign

0.25

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over