chr21-41246062-T-C

Position:

• chr21-41246062-T-C

Variant summary

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

The NM_012105.5(BACE2):​c.983T>C​(p.Leu328Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: BACE2 NM_012105.5 missense, splice_region
• Scores: Splicing: ADA: 0.1052
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20

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.983T>C	p.Leu328Pro	missense_variant, splice_region_variant	6/9	ENST00000330333.11
BACE2	NM_138991.3	c.983T>C	p.Leu328Pro	missense_variant, splice_region_variant	6/8
BACE2	NM_138992.3	c.983T>C	p.Leu328Pro	missense_variant, splice_region_variant	6/8
BACE2	XM_017028314.2	c.698T>C	p.Leu233Pro	missense_variant, splice_region_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACE2	ENST00000330333.11	c.983T>C	p.Leu328Pro	missense_variant, splice_region_variant	6/9	1	NM_012105.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

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

Apr 12, 2022

The c.983T>C (p.L328P) alteration is located in exon 6 (coding exon 6) of the BACE2 gene. This alteration results from a T to C substitution at nucleotide position 983, causing the leucine (L) at amino acid position 328 to be replaced by a proline (P). 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	0.23
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.99	D;B;D
Vest4		0.71
MutPred		0.63		Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);
MVP		0.59
MPC		1.7
ClinPred		0.77	D
GERP RS		4.0
Varity_R		0.49
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.25
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: chr21-42617989;