Genetic Variant NM_018171.5:c.1298C>T (chr12-105190099-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_018171.5(APPL2):c.1298C>T(p.Ala433Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,852 control chromosomes in the GnomAD database, including 31,285 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.18 ( 2581 hom., cov: 33)

Exomes 𝑓: 0.20 ( 28704 hom. )

Consequence

APPL2
NM_018171.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.48

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 (MetaRNN=0.00509274).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APPL2	NM_018171.5 link	c.1298C>T	p.Ala433Val	missense_variant	Exon 15 of 21	ENST00000258530.8	NP_060641.2	Q8NEU8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APPL2	ENST00000258530.8 link	c.1298C>T	p.Ala433Val	missense_variant	Exon 15 of 21	1	NM_018171.5	ENSP00000258530.3		Q8NEU8-1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26910

AN:

152046

Hom.:

2582

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.173

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.194

Gnomad OTH

AF:

0.176

GnomAD3 exomes

AF:

0.207

AC:

51908

AN:

251158

Hom.:

5561

AF XY:

0.203

AC XY:

27564

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.264

Gnomad ASJ exome

AF:

0.182

Gnomad EAS exome

AF:

0.253

Gnomad SAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.236

Gnomad NFE exome

AF:

0.201

Gnomad OTH exome

AF:

0.201

GnomAD4 exome

AF:

0.196

AC:

286997

AN:

1461688

Hom.:

28704

Cov.:

AF XY:

0.195

AC XY:

142120

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.110

Gnomad4 AMR exome

AF:

0.254

Gnomad4 ASJ exome

AF:

0.174

Gnomad4 EAS exome

AF:

0.231

Gnomad4 SAS exome

AF:

0.174

Gnomad4 FIN exome

AF:

0.228

Gnomad4 NFE exome

AF:

0.197

Gnomad4 OTH exome

AF:

0.192

GnomAD4 genome

AF:

0.177

AC:

26905

AN:

152164

Hom.:

2581

Cov.:

AF XY:

0.180

AC XY:

13359

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.110

Gnomad4 AMR

AF:

0.210

Gnomad4 ASJ

AF:

0.173

Gnomad4 EAS

AF:

0.252

Gnomad4 SAS

AF:

0.178

Gnomad4 FIN

AF:

0.233

Gnomad4 NFE

AF:

0.194

Gnomad4 OTH

AF:

0.173

Alfa

AF:

0.192

Hom.:

7518

Bravo

AF:

0.177

TwinsUK

AF:

0.189

AC:

702

ALSPAC

AF:

0.196

AC:

754

ExAC

AF:

0.203

AC:

24612

Asia WGS

AF:

0.234

AC:

811

AN:

3478

EpiCase

AF:

0.190

EpiControl

AF:

0.203

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

T;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.78

T;T;T

MetaRNN

Benign

0.0051

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.039

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.025

B;.;.

Vest4

0.055

MPC

0.14

ClinPred

0.0099

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.24

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