21-41237710-C-G

Position:

• chr21-41237710-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000330333.11(BACE2):​c.599C>G​(p.Ala200Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BACE2 ENST00000330333.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BACE2	NM_012105.5	c.599C>G	p.Ala200Gly	missense_variant	3/9	ENST00000330333.11	NP_036237.2
BACE2	NM_138991.3	c.599C>G	p.Ala200Gly	missense_variant	3/8		NP_620476.1
BACE2	NM_138992.3	c.599C>G	p.Ala200Gly	missense_variant	3/8		NP_620477.1
BACE2	XM_017028314.2	c.314C>G	p.Ala105Gly	missense_variant	4/10		XP_016883803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BACE2	ENST00000330333.11	c.599C>G	p.Ala200Gly	missense_variant	3/9	1	NM_012105.5	ENSP00000332979	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Mar 14, 2023

The c.599C>G (p.A200G) alteration is located in exon 3 (coding exon 3) of the BACE2 gene. This alteration results from a C to G substitution at nucleotide position 599, causing the alanine (A) at amino acid position 200 to be replaced by a glycine (G). 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	0.24
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.87	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		1.0	D;B;D
Vest4		0.79
MutPred		0.79		Loss of catalytic residue at A200 (P = 0.012);Loss of catalytic residue at A200 (P = 0.012);Loss of catalytic residue at A200 (P = 0.012);
MVP		0.41
MPC		1.4
ClinPred		0.84	D
GERP RS		5.6
Varity_R		0.52
gMVP		0.94

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: chr21-42609637;