rs200237364

Variant names:

• chr19-46838692-C-T
• rs200237364
• NM_004069.6:c.327+48G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-46838692-C-T
• chr19-46838692-C-A
• chr19-46838692-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004069.6(AP2S1):​c.327+48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,604,310 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (46 hom.)
• Consequence: AP2S1 NM_004069.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.42
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 19-46838692-C-T is Benign according to our data. Variant chr19-46838692-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1697839.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 563 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.327+48G>A		intron	N/A	NP_004060.2	P53680-1
	AP2S1	NM_001301076.3		c.375+48G>A		intron	N/A	NP_001288005.1	M0QYZ2
	AP2S1	NM_001301078.3		c.369+48G>A		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.327+48G>A		intron	N/A	ENSP00000263270.6	P53680-1
	AP2S1	ENST00000597020.5	TSL:1	c.267+48G>A		intron	N/A	ENSP00000470235.1	M0QZ21
	AP2S1	ENST00000600964.1	TSL:1	n.81+48G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 562 AN: 152140 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00428 AC: 1064 AN: 248534 AF XY: 0.00425

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00612

GnomAD4 exome AF: 0.00303 AC: 4402 AN: 1452052 Hom.: 46 Cov.: 30 AF XY: 0.00322 AC XY: 2324 AN XY: 722790

African (AFR) AF: 0.000271 AC: 9 AN: 33266

American (AMR) AF: 0.000337 AC: 15 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00227 AC: 59 AN: 25946

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39628

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85752

European-Finnish (FIN) AF: 0.0226 AC: 1203 AN: 53324

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5730

European-Non Finnish (NFE) AF: 0.00267 AC: 2952 AN: 1103800

Other (OTH) AF: 0.00268 AC: 161 AN: 60052

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152258 Hom.: 9 Cov.: 31 AF XY: 0.00402 AC XY: 299 AN XY: 74430

African (AFR) AF: 0.000168 AC: 7 AN: 41560

American (AMR) AF: 0.000916 AC: 14 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0185 AC: 196 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00494 AC: 336 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00626 Hom.: 2

Bravo AF: 0.00170

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.13
DANN	Benign	0.57
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs200237364; hg19: chr19-47341949;