rs1357559883

Variant names:

• chr11-130121671-G-A
• rs1357559883
• NM_001142276.2:c.574G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001142276.2(APLP2):​c.574G>A​(p.Val192Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: APLP2 NM_001142276.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65
• Publications: 1 publications found

Genes affected

APLP2 (HGNC:598): (amyloid beta precursor like protein 2) This gene encodes amyloid precursor- like protein 2 (APLP2), which is a member of the APP (amyloid precursor protein) family including APP, APLP1 and APLP2. This protein is ubiquitously expressed. It contains heparin-, copper- and zinc- binding domains at the N-terminus, BPTI/Kunitz inhibitor and E2 domains in the middle region, and transmembrane and intracellular domains at the C-terminus. This protein interacts with major histocompatibility complex (MHC) class I molecules. The synergy of this protein and the APP is required to mediate neuromuscular transmission, spatial learning and synaptic plasticity. This protein has been implicated in the pathogenesis of Alzheimer's disease. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33230507).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APLP2	NM_001142276.2	MANE Select	c.574G>A	p.Val192Ile	missense	Exon 5 of 17	NP_001135748.1	Q06481-3
	APLP2	NM_001642.3		c.574G>A	p.Val192Ile	missense	Exon 5 of 18	NP_001633.1	Q06481-1
	APLP2	NM_001243299.2		c.604G>A	p.Val202Ile	missense	Exon 5 of 17	NP_001230228.1	Q06481-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APLP2	ENST00000338167.10	TSL:1 MANE Select	c.574G>A	p.Val192Ile	missense	Exon 5 of 17	ENSP00000345444.5	Q06481-3
	APLP2	ENST00000263574.9	TSL:1	c.574G>A	p.Val192Ile	missense	Exon 5 of 18	ENSP00000263574.5	Q06481-1
	APLP2	ENST00000528499.5	TSL:1	c.574G>A	p.Val192Ile	missense	Exon 5 of 16	ENSP00000435914.1	Q06481-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251442 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Benign	0.86
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.43	N
PhyloP100		3.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.24
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.052	B
Vest4		0.18
MutPred		0.46		Loss of sheet (P = 0.1907)
MVP		0.45
MPC		0.28
ClinPred		0.37	T
GERP RS		4.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.059
gMVP		0.096
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1357559883; hg19: chr11-129991566;