AP1S2 p.Ser96Ser

Variant names:

• chrX-15845902-C-C
• NM_001272071.2:c.

Your query was ambiguous. Multiple possible variants found:

• chrX-15845903--
• chrX-15845903-A-G
• chrX-15845904-CT-GA
• chrX-15845903-ACT-GGA
• chrX-15845903-ACT-TGA
• chrX-15845903-ACT-CGA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001272071.2(AP1S2):​c. variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: AP1S2 NM_001272071.2 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.467
• Publications: 0 publications found

Genes affected

AP1S2 (HGNC:560): (adaptor related protein complex 1 subunit sigma 2) Adaptor protein complex 1 is found at the cytoplasmic face of coated vesicles located at the Golgi complex, where it mediates both the recruitment of clathrin to the membrane and the recognition of sorting signals within the cytosolic tails of transmembrane receptors. This complex is a heterotetramer composed of two large, one medium, and one small adaptin subunit. The protein encoded by this gene serves as the small subunit of this complex and is a member of the adaptin protein family. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

AP1S2 Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability 5

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• X-linked syndromic complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• fried syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• autism spectrum disorder

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.22567287 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7, offset of 0 (no position change), new splice context is: agtGTgagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001272071.2. 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
	AP1S2	NM_001272071.2	MANE Select	c.		splice_donor intron	N/A	NP_001259000.1	A0A5F9ZHW1
	AP1S2	NM_001369007.1		c.		splice_donor intron	N/A	NP_001355936.1	A6NH01
	AP1S2	NM_001440864.1		c.		splice_donor intron	N/A	NP_001427793.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1S2	ENST00000672987.1	MANE Select	c.		splice_donor intron	N/A	ENSP00000500695.1	A0A5F9ZHW1
	AP1S2	ENST00000329235.6	TSL:1	c.		splice_donor intron	N/A	ENSP00000328789.2	P56377-1
	AP1S2	ENST00000545766.7	TSL:1	c.		splice_donor intron	N/A	ENSP00000444957.3	F6SFB5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-15864025;