rs935251

chr12-105187140-G-Achr12-105187140-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018171.5(APPL2):c.1634+1133C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 151,952 control chromosomes in the GnomAD database, including 24,500 homozygotes. 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: 𝑓 0.55 (24500 hom., cov: 32)
• Consequence: APPL2 NM_018171.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.338

Genes affected

APPL2 (HGNC:18242): (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2) The protein encoded by this gene is one of two effectors of the small GTPase RAB5A/Rab5, which are involved in a signal transduction pathway. Both effectors contain an N-terminal Bin/Amphiphysin/Rvs (BAR) domain, a central pleckstrin homology (PH) domain, and a C-terminal phosphotyrosine binding (PTB) domain, and they bind the Rab5 through the BAR domain. They are associated with endosomal membranes and can be translocated to the nucleus in response to the EGF stimulus. They interact with the NuRD/MeCP1 complex (nucleosome remodeling and deacetylase /methyl-CpG-binding protein 1 complex) and are required for efficient cell proliferation. A chromosomal aberration t(12;22)(q24.1;q13.3) involving this gene and the PSAP2 gene results in 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL2	NM_018171.5	c.1634+1133C>T		intron_variant		ENST00000258530.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL2	ENST00000258530.8	c.1634+1133C>T		intron_variant		1	NM_018171.5	P1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83164 AN: 151832 Hom.: 24515 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.685

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.595

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.547 AC: 83160 AN: 151952 Hom.: 24500 Cov.: 32 AF XY: 0.554 AC XY: 41159 AN XY: 74320

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.622

Gnomad4 ASJ AF: 0.737

Gnomad4 EAS AF: 0.675

Gnomad4 SAS AF: 0.672

Gnomad4 FIN AF: 0.670

Gnomad4 NFE AF: 0.626

Gnomad4 OTH AF: 0.589

Alfa AF: 0.626 Hom.: 60667

Bravo AF: 0.533

Asia WGS AF: 0.611 AC: 2120 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.7
Dann	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs935251; hg19: chr12-105580918;