11-130070075-A-G

Variant names:

• chr11-130070075-A-G
• rs776174946
• NM_001142276.2:c.98A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001382542.1(APLP2):​c.-73A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000136 in 1,474,202 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: APLP2 NM_001382542.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.59
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382542.1. 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.98A>G	p.Tyr33Cys	missense	Exon 1 of 17	NP_001135748.1	Q06481-3
	APLP2	NM_001382542.1		c.-73A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001369471.1
	APLP2	NM_001642.3		c.98A>G	p.Tyr33Cys	missense	Exon 1 of 18	NP_001633.1	Q06481-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APLP2	ENST00000338167.10	TSL:1 MANE Select	c.98A>G	p.Tyr33Cys	missense	Exon 1 of 17	ENSP00000345444.5	Q06481-3
	APLP2	ENST00000263574.9	TSL:1	c.98A>G	p.Tyr33Cys	missense	Exon 1 of 18	ENSP00000263574.5	Q06481-1
	APLP2	ENST00000528499.5	TSL:1	c.98A>G	p.Tyr33Cys	missense	Exon 1 of 16	ENSP00000435914.1	Q06481-4

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151580 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.56e-7 AC: 1 AN: 1322622 Hom.: 0 Cov.: 30 AF XY: 0.00000153 AC XY: 1 AN XY: 653360

African (AFR) AF: 0.00 AC: 0 AN: 26646

American (AMR) AF: 0.00 AC: 0 AN: 27172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21952

East Asian (EAS) AF: 0.00 AC: 0 AN: 29146

South Asian (SAS) AF: 0.00 AC: 0 AN: 72848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4210

European-Non Finnish (NFE) AF: 9.50e-7 AC: 1 AN: 1052916

Other (OTH) AF: 0.00 AC: 0 AN: 54352

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151580 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74056

African (AFR) AF: 0.0000242 AC: 1 AN: 41276

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67876

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.056
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.3	L
PhyloP100		3.6
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.44		Loss of catalytic residue at L28 (P = 0.1771)
MVP		0.82
MPC		0.56
ClinPred		0.86	D
GERP RS		3.8
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.73
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs776174946; hg19: chr11-129939970;