21-41168358-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012105.5(BACE2):c.95C>A(p.Pro32His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BACE2 NM_012105.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3350467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BACE2	NM_012105.5	c.95C>A	p.Pro32His	missense_variant	1/9	ENST00000330333.11
BACE2	NM_138991.3	c.95C>A	p.Pro32His	missense_variant	1/8
BACE2	NM_138992.3	c.95C>A	p.Pro32His	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACE2	ENST00000330333.11	c.95C>A	p.Pro32His	missense_variant	1/9	1	NM_012105.5	P1
BACE2	ENST00000347667.5	c.95C>A	p.Pro32His	missense_variant	1/8	1
BACE2	ENST00000328735.10	c.95C>A	p.Pro32His	missense_variant	1/8	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1239868 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 608270

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Mar 11, 2024

The c.95C>A (p.P32H) alteration is located in exon 1 (coding exon 1) of the BACE2 gene. This alteration results from a C to A substitution at nucleotide position 95, causing the proline (P) at amino acid position 32 to be replaced by a histidine (H). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.97	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;T;D
Polyphen		0.94	P;D;D
Vest4		0.18
MutPred		0.49		Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP		0.40
MPC		1.6
ClinPred		0.61	D
GERP RS		1.8
Varity_R		0.30
gMVP		0.89

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: chr21-42540285;