19-46838377-C-G

Variant names:

• chr19-46838377-C-G
• rs76955283
• NM_004069.6:c.*70G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_004069.6(AP2S1):​c.*70G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000369 in 1,354,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: AP2S1 NM_004069.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS2: High AC in GnomAdExome4 at 5 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.*70G>C		3_prime_UTR	Exon 5 of 5	NP_004060.2	P53680-1
	AP2S1	NM_001301076.3		c.*70G>C		3_prime_UTR	Exon 5 of 5	NP_001288005.1	M0QYZ2
	AP2S1	NM_001301078.3		c.*70G>C		3_prime_UTR	Exon 5 of 5	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.*70G>C		3_prime_UTR	Exon 5 of 5	ENSP00000263270.6	P53680-1
	AP2S1	ENST00000597020.5	TSL:1	c.*70G>C		3_prime_UTR	Exon 4 of 4	ENSP00000470235.1	M0QZ21
	AP2S1	ENST00000600964.1	TSL:1	n.253G>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000369 AC: 5 AN: 1354306 Hom.: 0 Cov.: 21 AF XY: 0.00000295 AC XY: 2 AN XY: 677884

African (AFR) AF: 0.00 AC: 0 AN: 31070

American (AMR) AF: 0.00 AC: 0 AN: 42736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25292

East Asian (EAS) AF: 0.00 AC: 0 AN: 38578

South Asian (SAS) AF: 0.00 AC: 0 AN: 83004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 0.00000490 AC: 5 AN: 1019568

Other (OTH) AF: 0.00 AC: 0 AN: 56728

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.6
DANN	Benign	0.80
PhyloP100		-1.0

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: rs76955283; hg19: chr19-47341634;