12-105223192-G-A

Variant names:

• chr12-105223192-G-A
• rs1196768
• NM_018171.5:c.154-5467C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018171.5(APPL2):​c.154-5467C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 152,012 control chromosomes in the GnomAD database, including 11,574 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 0.38 (11574 hom., cov: 32)
• Consequence: APPL2 NM_018171.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.739
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APPL2	NM_018171.5	c.154-5467C>T		intron_variant	Intron 2 of 20	ENST00000258530.8	NP_060641.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APPL2	ENST00000258530.8	c.154-5467C>T		intron_variant	Intron 2 of 20	1	NM_018171.5	ENSP00000258530.3

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57260 AN: 151894 Hom.: 11584 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.542

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.424

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

GnomAD4 genome AF: 0.377 AC: 57256 AN: 152012 Hom.: 11574 Cov.: 32 AF XY: 0.380 AC XY: 28263 AN XY: 74308

African (AFR) AF: 0.220 AC: 9135 AN: 41498

American (AMR) AF: 0.420 AC: 6414 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1964 AN: 3472

East Asian (EAS) AF: 0.436 AC: 2238 AN: 5132

South Asian (SAS) AF: 0.480 AC: 2307 AN: 4802

European-Finnish (FIN) AF: 0.432 AC: 4570 AN: 10582

Middle Eastern (MID) AF: 0.541 AC: 157 AN: 290

European-Non Finnish (NFE) AF: 0.431 AC: 29317 AN: 67950

Other (OTH) AF: 0.419 AC: 882 AN: 2104

Alfa AF: 0.408 Hom.: 22196

Bravo AF: 0.366

Asia WGS AF: 0.374 AC: 1303 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.68
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism (auto)

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: rs1196768; hg19: chr12-105616970;