NM_001142276.2:c.106G>T

Variant names:

• chr11-130109429-G-T
• NM_001142276.2:c.106G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001142276.2(APLP2):​c.106G>T​(p.Ala36Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APLP2 NM_001142276.2 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.106G>T	p.Ala36Ser	missense splice_region	Exon 2 of 17	NP_001135748.1	Q06481-3
	APLP2	NM_001642.3		c.106G>T	p.Ala36Ser	missense splice_region	Exon 2 of 18	NP_001633.1	Q06481-1
	APLP2	NM_001243299.2		c.136G>T	p.Ala46Ser	missense splice_region	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.106G>T	p.Ala36Ser	missense splice_region	Exon 2 of 17	ENSP00000345444.5	Q06481-3
	APLP2	ENST00000263574.9	TSL:1	c.106G>T	p.Ala36Ser	missense splice_region	Exon 2 of 18	ENSP00000263574.5	Q06481-1
	APLP2	ENST00000528499.5	TSL:1	c.106G>T	p.Ala36Ser	missense splice_region	Exon 2 of 16	ENSP00000435914.1	Q06481-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	1.1	L
PhyloP100		9.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.41
Sift	Benign	0.067	T
Sift4G	Uncertain	0.012	D
Polyphen		0.97	D
Vest4		0.57
MutPred		0.36		Gain of glycosylation at A36 (P = 0.0306)
MVP		0.74
MPC		0.55
ClinPred		0.76	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.59
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.080		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

hg19: chr11-129979324;