rs1196744

chr12-105197044-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.1052+721C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 151,940 control chromosomes in the GnomAD database, including 29,404 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 0.60 (29404 hom., cov: 30)
• Consequence: APPL2 NM_018171.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460

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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL2	NM_018171.5	c.1052+721C>G		intron_variant		ENST00000258530.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL2	ENST00000258530.8	c.1052+721C>G		intron_variant		1	NM_018171.5	P1

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90493 AN: 151822 Hom.: 29417 Cov.: 30

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.899

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.638

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

GnomAD4 genome AF: 0.596 AC: 90496 AN: 151940 Hom.: 29404 Cov.: 30 AF XY: 0.607 AC XY: 45045 AN XY: 74258

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.724

Gnomad4 ASJ AF: 0.745

Gnomad4 EAS AF: 0.899

Gnomad4 SAS AF: 0.790

Gnomad4 FIN AF: 0.723

Gnomad4 NFE AF: 0.670

Gnomad4 OTH AF: 0.633

Alfa AF: 0.617 Hom.: 3763

Bravo AF: 0.584

Asia WGS AF: 0.786 AC: 2731 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.62
Dann	Benign	0.48

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: rs1196744; hg19: chr12-105590822;