chr15-29054173-A-G

Variant names:

• chr15-29054173-A-G
• rs2041756198
• NM_001353788.2:c.289A>G

Variant summary

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

The NM_001353788.2(APBA2):​c.289A>G​(p.Ile97Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,870 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: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: APBA2 NM_001353788.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• Publications: 0 publications found

Genes affected

APBA2 (HGNC:579): (amyloid beta precursor protein binding family A member 2) The protein encoded by this gene is a member of the X11 protein family. It is a neuronal adapter protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). It stabilizes APP and inhibits production of proteolytic APP fragments including the A beta peptide that is deposited in the brains of Alzheimer's disease patients. This gene product is believed to be involved in signal transduction processes. It is also regarded as a putative vesicular trafficking protein in the brain that can form a complex with the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion. [provided by RefSeq, Jul 2017]

APBA2 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11662829).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353788.2. 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
	APBA2	NM_001353788.2	MANE Select	c.289A>G	p.Ile97Val	missense	Exon 4 of 15	NP_001340717.1	Q99767-1
	APBA2	NM_001353789.2		c.289A>G	p.Ile97Val	missense	Exon 4 of 15	NP_001340718.1	Q99767-1
	APBA2	NM_001353790.2		c.289A>G	p.Ile97Val	missense	Exon 4 of 15	NP_001340719.1	Q99767-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APBA2	ENST00000683413.1	MANE Select	c.289A>G	p.Ile97Val	missense	Exon 4 of 15	ENSP00000507394.1	Q99767-1
	APBA2	ENST00000558259.5	TSL:1	c.289A>G	p.Ile97Val	missense	Exon 3 of 14	ENSP00000454171.1	Q99767-1
	APBA2	ENST00000411764.5	TSL:1	c.289A>G	p.Ile97Val	missense	Exon 3 of 13	ENSP00000409312.1	Q99767-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727236

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: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

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	0.064
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.094
Sift	Benign	0.37	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.086
MutPred		0.23		Gain of sheet (P = 0.1539)
MVP		0.54
MPC		0.34
ClinPred		0.23	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.022
gMVP		0.055
Mutation Taster		=93/7	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: rs2041756198; hg19: chr15-29346376;