chr12-105190099-G-A

Variant names:

• chr12-105190099-G-A
• rs2272495
• NM_018171.5:c.1298C>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.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. 13/21 in silico tools predict 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 (2581 hom., cov: 33)
  • Exomes 𝑓: 0.20 (28704 hom.)
• Consequence: APPL2 NM_018171.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 26 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 (MetaRNN=0.00509274).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.24 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.1298C>T	p.Ala433Val	missense	Exon 15 of 21	NP_060641.2
	APPL2	NM_001251904.2		c.1316C>T	p.Ala439Val	missense	Exon 15 of 21	NP_001238833.1
	APPL2	NM_001251905.2		c.1169C>T	p.Ala390Val	missense	Exon 15 of 21	NP_001238834.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APPL2	ENST00000258530.8	TSL:1 MANE Select	c.1298C>T	p.Ala433Val	missense	Exon 15 of 21	ENSP00000258530.3
	APPL2	ENST00000547439.5	TSL:1	n.*583C>T		non_coding_transcript_exon	Exon 15 of 21	ENSP00000449410.1
	APPL2	ENST00000547809.5	TSL:1	n.1308C>T		non_coding_transcript_exon	Exon 15 of 18

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26910 AN: 152046 Hom.: 2582 Cov.: 33

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

GnomAD2 exomes AF: 0.207 AC: 51908 AN: 251158 AF XY: 0.203

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 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.: 34 AF XY: 0.195 AC XY: 142120 AN XY: 727146

African (AFR) AF: 0.110 AC: 3678 AN: 33478

American (AMR) AF: 0.254 AC: 11357 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4544 AN: 26134

East Asian (EAS) AF: 0.231 AC: 9190 AN: 39700

South Asian (SAS) AF: 0.174 AC: 14978 AN: 86242

European-Finnish (FIN) AF: 0.228 AC: 12159 AN: 53386

Middle Eastern (MID) AF: 0.151 AC: 870 AN: 5764

European-Non Finnish (NFE) AF: 0.197 AC: 218600 AN: 1111916

Other (OTH) AF: 0.192 AC: 11621 AN: 60388

GnomAD4 genome AF: 0.177 AC: 26905 AN: 152164 Hom.: 2581 Cov.: 33 AF XY: 0.180 AC XY: 13359 AN XY: 74396

African (AFR) AF: 0.110 AC: 4553 AN: 41530

American (AMR) AF: 0.210 AC: 3213 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3472

East Asian (EAS) AF: 0.252 AC: 1304 AN: 5178

South Asian (SAS) AF: 0.178 AC: 860 AN: 4826

European-Finnish (FIN) AF: 0.233 AC: 2461 AN: 10578

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.194 AC: 13182 AN: 67984

Other (OTH) AF: 0.173 AC: 366 AN: 2112

Alfa AF: 0.189 Hom.: 11098

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.039
Sift	Benign	0.13	T
Sift4G	Benign	0.26	T
Polyphen		0.025	B
Vest4		0.055
MPC		0.14
ClinPred		0.0099	T
GERP RS		4.5
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.24
Mutation Taster		=97/3	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: rs2272495; hg19: chr12-105583877; COSMIC: COSV51588096; COSMIC: COSV51588096;