chr19-46839460-C-T

Variant names:

• chr19-46839460-C-T
• rs312186
• NM_004069.6:c.267+5G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001301076.3(AP2S1):​c.315+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_001301076.3 splice_region, intron
• Scores: Splicing: ADA: 0.2398
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.19
• Publications: 13 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.84).
• BP6: Variant 19-46839460-C-T is Benign according to our data. Variant chr19-46839460-C-T is described in ClinVar as Benign. ClinVar VariationId is 259227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301076.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2S1	NM_004069.6	MANE Select	c.267+5G>A		splice_region intron	N/A	NP_004060.2
	AP2S1	NM_001301076.3		c.315+5G>A		splice_region intron	N/A	NP_001288005.1
	AP2S1	NM_001301078.3		c.309+5G>A		splice_region intron	N/A	NP_001288007.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2S1	ENST00000263270.11	TSL:1 MANE Select	c.267+5G>A		splice_region intron	N/A	ENSP00000263270.6
	AP2S1	ENST00000597020.5	TSL:1	c.207+5G>A		splice_region intron	N/A	ENSP00000470235.1
	AP2S1	ENST00000960448.1		c.384+5G>A		splice_region intron	N/A	ENSP00000630507.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 36762 AN: 150914 Hom.: 5801 Cov.: 28

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

GnomAD2 exomes AF: 0.250 AC: 62919 AN: 251404 AF XY: 0.241

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 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.: 49 AF XY: 0.179 AC XY: 130088 AN XY: 725714

African (AFR) AF: 0.378 AC: 12593 AN: 33314

American (AMR) AF: 0.449 AC: 20027 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 6014 AN: 26068

East Asian (EAS) AF: 0.485 AC: 19152 AN: 39472

South Asian (SAS) AF: 0.322 AC: 27766 AN: 86116

European-Finnish (FIN) AF: 0.110 AC: 5844 AN: 53244

Middle Eastern (MID) AF: 0.226 AC: 1249 AN: 5516

European-Non Finnish (NFE) AF: 0.137 AC: 152037 AN: 1110136

Other (OTH) AF: 0.209 AC: 12604 AN: 60166

GnomAD4 genome AF: 0.244 AC: 36821 AN: 151036 Hom.: 5813 Cov.: 28 AF XY: 0.246 AC XY: 18121 AN XY: 73720

African (AFR) AF: 0.372 AC: 15285 AN: 41048

American (AMR) AF: 0.364 AC: 5505 AN: 15110

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 795 AN: 3464

East Asian (EAS) AF: 0.504 AC: 2572 AN: 5102

South Asian (SAS) AF: 0.349 AC: 1672 AN: 4790

European-Finnish (FIN) AF: 0.103 AC: 1074 AN: 10454

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9208 AN: 67786

Other (OTH) AF: 0.241 AC: 504 AN: 2090

Alfa AF: 0.189 Hom.: 5659

Bravo AF: 0.271

Asia WGS AF: 0.453 AC: 1572 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.4
DANN	Benign	0.49
PhyloP100		2.2
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs312186; hg19: chr19-47342717; COSMIC: COSV54383928; COSMIC: COSV54383928;