19-46838627-C-A

Variant names:

• chr19-46838627-C-A
• rs147698652
• NM_004069.6:c.328-79G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004069.6(AP2S1):​c.328-79G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,575,292 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (26 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (34 hom.)
• Consequence: AP2S1 NM_004069.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.310
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-46838627-C-A is Benign according to our data. Variant chr19-46838627-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1198579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1598/152270) while in subpopulation AFR AF = 0.0368 (1531/41560). AF 95% confidence interval is 0.0353. There are 26 homozygotes in GnomAd4. There are 742 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1598 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.328-79G>T		intron	N/A	NP_004060.2	P53680-1
	AP2S1	NM_001301076.3		c.376-79G>T		intron	N/A	NP_001288005.1	M0QYZ2
	AP2S1	NM_001301078.3		c.370-79G>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.328-79G>T		intron	N/A	ENSP00000263270.6	P53680-1
	AP2S1	ENST00000597020.5	TSL:1	c.268-79G>T		intron	N/A	ENSP00000470235.1	M0QZ21
	AP2S1	ENST00000600964.1	TSL:1	n.82-79G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1588 AN: 152152 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00109 AC: 1556 AN: 1423022 Hom.: 34 Cov.: 26 AF XY: 0.000897 AC XY: 636 AN XY: 709044

African (AFR) AF: 0.0384 AC: 1248 AN: 32474

American (AMR) AF: 0.00211 AC: 93 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 39358

South Asian (SAS) AF: 0.0000704 AC: 6 AN: 85212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53166

Middle Eastern (MID) AF: 0.00229 AC: 13 AN: 5682

European-Non Finnish (NFE) AF: 0.0000390 AC: 42 AN: 1078290

Other (OTH) AF: 0.00261 AC: 154 AN: 59022

GnomAD4 genome AF: 0.0105 AC: 1598 AN: 152270 Hom.: 26 Cov.: 31 AF XY: 0.00997 AC XY: 742 AN XY: 74442

African (AFR) AF: 0.0368 AC: 1531 AN: 41560

American (AMR) AF: 0.00327 AC: 50 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00876 Hom.: 2

Bravo AF: 0.0115

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.82
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs147698652; hg19: chr19-47341884;