Variant chr12-105176263-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018171.5(APPL2):c.1813-181G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 574,800 control chromosomes in the GnomAD database, including 6,791 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 0.18 ( 3451 hom., cov: 32)

Exomes 𝑓: 0.11 ( 3340 hom. )

Consequence

APPL2
NM_018171.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.381

Variant links:

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]

APPL2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APPL2	NM_018171.5 linkuse as main transcript	c.1813-181G>A		intron_variant		ENST00000258530.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APPL2	ENST00000258530.8 linkuse as main transcript	c.1813-181G>A		intron_variant		1	NM_018171.5	P1	Q8NEU8-1

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

27033

AN:

151988

Hom.:

3429

Cov.:

show subpopulations

Gnomad AFR

AF:

0.359

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.0343

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.146

Gnomad FIN

AF:

0.0828

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0928

Gnomad OTH

AF:

0.152

GnomAD3 exomes

AF:

0.136

AC:

4283

AN:

31528

Hom.:

323

AF XY:

0.130

AC XY:

2321

AN XY:

17838

show subpopulations

Gnomad AFR exome

AF:

0.361

Gnomad AMR exome

AF:

0.216

Gnomad ASJ exome

AF:

0.0380

Gnomad EAS exome

AF:

0.251

Gnomad SAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.111

AC:

46805

AN:

422694

Hom.:

3340

Cov.:

AF XY:

0.110

AC XY:

24789

AN XY:

225232

show subpopulations

Gnomad4 AFR exome

AF:

0.358

Gnomad4 AMR exome

AF:

0.195

Gnomad4 ASJ exome

AF:

0.0356

Gnomad4 EAS exome

AF:

0.239

Gnomad4 SAS exome

AF:

0.124

Gnomad4 FIN exome

AF:

0.0835

Gnomad4 NFE exome

AF:

0.0917

Gnomad4 OTH exome

AF:

0.120

GnomAD4 genome

AF:

0.178

AC:

27098

AN:

152106

Hom.:

3451

Cov.:

AF XY:

0.179

AC XY:

13278

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.360

Gnomad4 AMR

AF:

0.171

Gnomad4 ASJ

AF:

0.0343

Gnomad4 EAS

AF:

0.226

Gnomad4 SAS

AF:

0.146

Gnomad4 FIN

AF:

0.0828

Gnomad4 NFE

AF:

0.0928

Gnomad4 OTH

AF:

0.152

Alfa

AF:

0.130

Hom.:

416

Bravo

AF:

0.192

Asia WGS

AF:

0.210

AC:

727

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over