Genetic Variant APPL2:n.*1761T>C (chr12-105173833-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000547439.5(APPL2):n.*1761T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 152,456 control chromosomes in the GnomAD database, including 19,304 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 ( 19249 hom., cov: 32)

Exomes 𝑓: 0.49 ( 55 hom. )

Consequence

APPL2
ENST00000547439.5 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.826

Publications

13 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APPL2	NM_018171.5 link	c.*481T>C		3_prime_UTR_variant	Exon 21 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.*481T>C		3_prime_UTR_variant	Exon 21 of 21	1	NM_018171.5	ENSP00000258530.3		Q8NEU8-1

Frequencies

GnomAD3 genomes

AF:

0.501

AC:

76111

AN:

151942

Hom.:

19255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.412

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.511

Gnomad ASJ

AF:

0.680

Gnomad EAS

AF:

0.422

Gnomad SAS

AF:

0.609

Gnomad FIN

AF:

0.577

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.530

Gnomad OTH

AF:

0.527

GnomAD4 exome

AF:

0.495

AC:

196

AN:

396

Hom.:

Cov.:

AF XY:

0.481

AC XY:

126

AN XY:

262

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.833

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

0.417

AC:

AN:

South Asian (SAS)

AF:

0.438

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.480

AC:

164

AN:

342

Other (OTH)

AF:

0.700

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.501

AC:

76130

AN:

152060

Hom.:

19249

Cov.:

AF XY:

0.503

AC XY:

37415

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.411

AC:

17044

AN:

41450

American (AMR)

AF:

0.511

AC:

7796

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.680

AC:

2361

AN:

3472

East Asian (EAS)

AF:

0.423

AC:

2185

AN:

5170

South Asian (SAS)

AF:

0.609

AC:

2939

AN:

4828

European-Finnish (FIN)

AF:

0.577

AC:

6084

AN:

10552

Middle Eastern (MID)

AF:

0.680

AC:

200

AN:

294

European-Non Finnish (NFE)

AF:

0.530

AC:

36038

AN:

68002

Other (OTH)

AF:

0.522

AC:

1102

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1943

3886

5829

7772

9715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

690

1380

2070

2760

3450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.521

Hom.:

57868

Bravo

AF:

0.486

Asia WGS

AF:

0.443

AC:

1543

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.83

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over