rs45527038

Variant names:

• chr19-46838570-G-A
• rs45527038
• NM_004069.6:c.328-22C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-46838570-G-A
• chr19-46838570-G-C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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 -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 VariationId is 1208917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1194 AD gene.

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.328-22C>T		intron	N/A	NP_004060.2	P53680-1
	AP2S1	NM_001301076.3		c.376-22C>T		intron	N/A	NP_001288005.1	M0QYZ2
	AP2S1	NM_001301078.3		c.370-22C>T		intron	N/A	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.328-22C>T		intron	N/A	ENSP00000263270.6	P53680-1
	AP2S1	ENST00000597020.5	TSL:1	c.268-22C>T		intron	N/A	ENSP00000470235.1	M0QZ21
	AP2S1	ENST00000600964.1	TSL:1	n.82-22C>T		intron	N/A

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

GnomAD2 exomes AF: 0.00798 AC: 2004 AN: 251066 AF XY: 0.00833

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 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

African (AFR) AF: 0.00230 AC: 77 AN: 33458

American (AMR) AF: 0.00689 AC: 308 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 409 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00634 AC: 547 AN: 86236

European-Finnish (FIN) AF: 0.00483 AC: 258 AN: 53406

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5768

European-Non Finnish (NFE) AF: 0.0111 AC: 12286 AN: 1111032

Other (OTH) AF: 0.0105 AC: 634 AN: 60332

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

African (AFR) AF: 0.00197 AC: 82 AN: 41588

American (AMR) AF: 0.0109 AC: 167 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00724 AC: 35 AN: 4832

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 791 AN: 68024

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0100 Hom.: 4

Bravo AF: 0.00826

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.021
DANN	Benign	0.83
PhyloP100		-4.3
Mutation Taster		=100/0	polymorphism

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

dbSNP: rs45527038; hg19: chr19-47341827;