chr12-105176263-C-T

Variant names:

• chr12-105176263-C-T
• rs10861360
• NM_018171.5:c.1813-181G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.381

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=-0.7).
• 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 rank	MANE	Protein	UniProt
APPL2	NM_018171.5	c.1813-181G>A		intron_variant	Intron 19 of 20	ENST00000258530.8	NP_060641.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APPL2	ENST00000258530.8	c.1813-181G>A		intron_variant	Intron 19 of 20	1	NM_018171.5	ENSP00000258530.3

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27033 AN: 151988 Hom.: 3429 Cov.: 32

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

GnomAD2 exomes AF: 0.136 AC: 4283 AN: 31528 AF XY: 0.130

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 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.: 4 AF XY: 0.110 AC XY: 24789 AN XY: 225232

Gnomad4 AFR exome AF: 0.358 AC: 3223 AN: 9002

Gnomad4 AMR exome AF: 0.195 AC: 2087 AN: 10702

Gnomad4 ASJ exome AF: 0.0356 AC: 504 AN: 14138

Gnomad4 EAS exome AF: 0.239 AC: 6089 AN: 25508

Gnomad4 SAS exome AF: 0.124 AC: 4811 AN: 38906

Gnomad4 FIN exome AF: 0.0835 AC: 2720 AN: 32574

Gnomad4 NFE exome AF: 0.0917 AC: 24157 AN: 263416

Gnomad4 Remaining exome AF: 0.120 AC: 2986 AN: 24918

GnomAD4 genome AF: 0.178 AC: 27098 AN: 152106 Hom.: 3451 Cov.: 32 AF XY: 0.179 AC XY: 13278 AN XY: 74366

Gnomad4 AFR AF: 0.360 AC: 0.35967 AN: 0.35967

Gnomad4 AMR AF: 0.171 AC: 0.171401 AN: 0.171401

Gnomad4 ASJ AF: 0.0343 AC: 0.0343137 AN: 0.0343137

Gnomad4 EAS AF: 0.226 AC: 0.225551 AN: 0.225551

Gnomad4 SAS AF: 0.146 AC: 0.146084 AN: 0.146084

Gnomad4 FIN AF: 0.0828 AC: 0.0828453 AN: 0.0828453

Gnomad4 NFE AF: 0.0928 AC: 0.0928017 AN: 0.0928017

Gnomad4 OTH AF: 0.152 AC: 0.151989 AN: 0.151989

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	15
DANN	Benign	0.88
Mutation Taster		=291/9	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

Publications

LitVar

Other links and lift over

dbSNP: rs10861360; hg19: chr12-105570041; COSMIC: COSV51587962; COSMIC: COSV51587962;