NM_001142276.2:c.257A>T

Variant names:

• chr11-130109580-A-T
• rs146181031
• NM_001142276.2:c.257A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001142276.2(APLP2):​c.257A>T​(p.Glu86Val) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,613,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E86D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: APLP2 NM_001142276.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 7 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.257A>T	p.Glu86Val	missense	Exon 2 of 17	NP_001135748.1	Q06481-3
	APLP2	NM_001642.3		c.257A>T	p.Glu86Val	missense	Exon 2 of 18	NP_001633.1	Q06481-1
	APLP2	NM_001243299.2		c.287A>T	p.Glu96Val	missense	Exon 2 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.257A>T	p.Glu86Val	missense	Exon 2 of 17	ENSP00000345444.5	Q06481-3
	APLP2	ENST00000263574.9	TSL:1	c.257A>T	p.Glu86Val	missense	Exon 2 of 18	ENSP00000263574.5	Q06481-1
	APLP2	ENST00000528499.5	TSL:1	c.257A>T	p.Glu86Val	missense	Exon 2 of 16	ENSP00000435914.1	Q06481-4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 37 AN: 249374 AF XY: 0.000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000142 AC: 208 AN: 1460916 Hom.: 0 Cov.: 30 AF XY: 0.000147 AC XY: 107 AN XY: 726748

African (AFR) AF: 0.0000300 AC: 1 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26106

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000175 AC: 194 AN: 1111622

Other (OTH) AF: 0.0000663 AC: 4 AN: 60324

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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	0.18
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.090	T
Polyphen		0.89	P
Vest4		0.58
MVP		0.87
MPC		0.54
ClinPred		0.55	D
GERP RS		5.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1
Varity_R		0.31
gMVP		0.58
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs146181031; hg19: chr11-129979475; COSMIC: COSV53839868; COSMIC: COSV53839868;