12-105187140-G-A

Variant names:

• chr12-105187140-G-A
• rs935251
• NM_018171.5:c.1634+1133C>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.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
• Publications: 5 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018171.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APPL2	NM_018171.5	MANE Select	c.1634+1133C>T		intron	N/A	NP_060641.2
	APPL2	NM_001251904.2		c.1652+1133C>T		intron	N/A	NP_001238833.1
	APPL2	NM_001251905.2		c.1505+1133C>T		intron	N/A	NP_001238834.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APPL2	ENST00000258530.8	TSL:1 MANE Select	c.1634+1133C>T		intron	N/A	ENSP00000258530.3
	APPL2	ENST00000547439.5	TSL:1	n.*919+1133C>T		intron	N/A	ENSP00000449410.1
	APPL2	ENST00000547809.5	TSL:1	n.1644+1133C>T		intron	N/A

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

African (AFR) AF: 0.307 AC: 12705 AN: 41394

American (AMR) AF: 0.622 AC: 9516 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2556 AN: 3470

East Asian (EAS) AF: 0.675 AC: 3491 AN: 5172

South Asian (SAS) AF: 0.672 AC: 3233 AN: 4812

European-Finnish (FIN) AF: 0.670 AC: 7067 AN: 10546

Middle Eastern (MID) AF: 0.692 AC: 202 AN: 292

European-Non Finnish (NFE) AF: 0.626 AC: 42524 AN: 67962

Other (OTH) AF: 0.589 AC: 1241 AN: 2108

Alfa AF: 0.605 Hom.: 90922

Bravo AF: 0.533

Asia WGS AF: 0.611 AC: 2120 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.53
PhyloP100		-0.34
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: rs935251; hg19: chr12-105580918;