NM_001142276.2:c.665A>G

Variant names:

• chr11-130121762-A-G
• rs565247278
• NM_001142276.2:c.665A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001142276.2(APLP2):​c.665A>G​(p.Glu222Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,331,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: APLP2 NM_001142276.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.68
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.087197274).
• BS2: High AC in GnomAd4 at 5 AD gene.

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.665A>G	p.Glu222Gly	missense	Exon 5 of 17	NP_001135748.1	Q06481-3
	APLP2	NM_001642.3		c.665A>G	p.Glu222Gly	missense	Exon 5 of 18	NP_001633.1	Q06481-1
	APLP2	NM_001243299.2		c.695A>G	p.Glu232Gly	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.665A>G	p.Glu222Gly	missense	Exon 5 of 17	ENSP00000345444.5	Q06481-3
	APLP2	ENST00000263574.9	TSL:1	c.665A>G	p.Glu222Gly	missense	Exon 5 of 18	ENSP00000263574.5	Q06481-1
	APLP2	ENST00000528499.5	TSL:1	c.665A>G	p.Glu222Gly	missense	Exon 5 of 16	ENSP00000435914.1	Q06481-4

Frequencies

GnomAD3 genomes AF: 0.0000418 AC: 5 AN: 119726 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000772

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000225

Gnomad FIN AF: 0.000113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000361

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251166 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000776 AC: 94 AN: 1211338 Hom.: 0 Cov.: 30 AF XY: 0.0000942 AC XY: 57 AN XY: 604886

African (AFR) AF: 0.00 AC: 0 AN: 22108

American (AMR) AF: 0.0000254 AC: 1 AN: 39300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23278

East Asian (EAS) AF: 0.00 AC: 0 AN: 35988

South Asian (SAS) AF: 0.000114 AC: 9 AN: 79154

European-Finnish (FIN) AF: 0.0000226 AC: 1 AN: 44204

Middle Eastern (MID) AF: 0.00112 AC: 5 AN: 4482

European-Non Finnish (NFE) AF: 0.0000734 AC: 67 AN: 913234

Other (OTH) AF: 0.000222 AC: 11 AN: 49590

GnomAD4 genome AF: 0.0000417 AC: 5 AN: 119796 Hom.: 0 Cov.: 31 AF XY: 0.0000508 AC XY: 3 AN XY: 59028

African (AFR) AF: 0.00 AC: 0 AN: 27736

American (AMR) AF: 0.0000771 AC: 1 AN: 12970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3050

East Asian (EAS) AF: 0.00 AC: 0 AN: 4658

South Asian (SAS) AF: 0.000225 AC: 1 AN: 4454

European-Finnish (FIN) AF: 0.000113 AC: 1 AN: 8820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.0000361 AC: 2 AN: 55416

Other (OTH) AF: 0.00 AC: 0 AN: 1632

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000764 AC: 8

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

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	0.094
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.087	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.28
Sift	Benign	0.061	T
Sift4G	Uncertain	0.014	D
Polyphen		0.32	B
Vest4		0.32
MVP		0.57
MPC		0.16
ClinPred		0.15	T
GERP RS		3.0
Varity_R		0.050
gMVP		0.11
Mutation Taster		=72/28	polymorphism

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: rs565247278; hg19: chr11-129991657;