21-41168548-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012105.5(BACE2):c.285G>C(p.Glu95Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BACE2 NM_012105.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95

Genes affected

BACE2 (HGNC:934): (beta-secretase 2) This gene encodes an integral membrane glycoprotein that functions as an aspartic protease. The encoded protein cleaves amyloid precursor protein into amyloid beta peptide, which is a critical step in the etiology of Alzheimer's disease and Down syndrome. The protein precursor is further processed into an active mature peptide. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BACE2	NM_012105.5	c.285G>C	p.Glu95Asp	missense_variant	1/9	ENST00000330333.11
BACE2	NM_138991.3	c.285G>C	p.Glu95Asp	missense_variant	1/8
BACE2	NM_138992.3	c.285G>C	p.Glu95Asp	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACE2	ENST00000330333.11	c.285G>C	p.Glu95Asp	missense_variant	1/9	1	NM_012105.5	P1
BACE2	ENST00000347667.5	c.285G>C	p.Glu95Asp	missense_variant	1/8	1
BACE2	ENST00000328735.10	c.285G>C	p.Glu95Asp	missense_variant	1/8	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.285G>C (p.E95D) alteration is located in exon 1 (coding exon 1) of the BACE2 gene. This alteration results from a G to C substitution at nucleotide position 285, causing the glutamic acid (E) at amino acid position 95 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.094
Sift	Uncertain	0.022	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.93	P;P;D
Vest4		0.41
MutPred		0.33		Loss of phosphorylation at Y92 (P = 0.0694);Loss of phosphorylation at Y92 (P = 0.0694);Loss of phosphorylation at Y92 (P = 0.0694);
MVP		0.56
MPC		0.47
ClinPred		0.93	D
GERP RS		3.1
Varity_R		0.65
gMVP		0.60

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-42540475;