12-105212892-C-T

Variant names:

• chr12-105212892-C-T
• rs752471
• NM_018171.5:c.286-1575G>A

Variant summary

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

The NM_018171.5(APPL2):​c.286-1575G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,046 control chromosomes in the GnomAD database, including 19,397 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 0.50 (19397 hom., cov: 33)
• Consequence: APPL2 NM_018171.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.345

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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APPL2	NM_018171.5	c.286-1575G>A		intron_variant	Intron 4 of 20	ENST00000258530.8	NP_060641.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APPL2	ENST00000258530.8	c.286-1575G>A		intron_variant	Intron 4 of 20	1	NM_018171.5	ENSP00000258530.3

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75643 AN: 151928 Hom.: 19390 Cov.: 33

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.537

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

GnomAD4 genome AF: 0.498 AC: 75679 AN: 152046 Hom.: 19397 Cov.: 33 AF XY: 0.504 AC XY: 37420 AN XY: 74316

Gnomad4 AFR AF: 0.369

Gnomad4 AMR AF: 0.569

Gnomad4 ASJ AF: 0.616

Gnomad4 EAS AF: 0.674

Gnomad4 SAS AF: 0.635

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.528

Gnomad4 OTH AF: 0.537

Alfa AF: 0.513 Hom.: 3414

Bravo AF: 0.491

Asia WGS AF: 0.607 AC: 2111 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.49

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: rs752471; hg19: chr12-105606670;