rs2252576

chr21-41243366-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012105.5(BACE2):c.748-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,578,428 control chromosomes in the GnomAD database, including 61,160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (13983 hom., cov: 32)
  • Exomes 𝑓: 0.24 (47177 hom.)
• Consequence: BACE2 NM_012105.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001374
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.359

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-41243366-C-T is Benign according to our data. Variant chr21-41243366-C-T is described in ClinVar as [Benign]. Clinvar id is 3059580.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BACE2	NM_012105.5	c.748-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000330333.11
BACE2	NM_138991.3	c.748-10C>T		splice_polypyrimidine_tract_variant, intron_variant
BACE2	NM_138992.3	c.748-10C>T		splice_polypyrimidine_tract_variant, intron_variant
BACE2	XM_017028314.2	c.463-10C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACE2	ENST00000330333.11	c.748-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_012105.5	P1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55071 AN: 151858 Hom.: 13951 Cov.: 32

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.0720

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.235 AC: 54424 AN: 231610 Hom.: 8904 AF XY: 0.228 AC XY: 28532 AN XY: 125302

Gnomad AFR exome AF: 0.731

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.273

Gnomad EAS exome AF: 0.0602

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.241 AC: 343972 AN: 1426452 Hom.: 47177 Cov.: 30 AF XY: 0.238 AC XY: 168736 AN XY: 707658

Gnomad4 AFR exome AF: 0.743

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.279

Gnomad4 EAS exome AF: 0.0712

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.197

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.363 AC: 55148 AN: 151976 Hom.: 13983 Cov.: 32 AF XY: 0.354 AC XY: 26273 AN XY: 74292

Gnomad4 AFR AF: 0.722

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.0720

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.237

Gnomad4 OTH AF: 0.338

Alfa AF: 0.270 Hom.: 10100

Bravo AF: 0.381

Asia WGS AF: 0.173 AC: 604 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BACE2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	3.9
Dann	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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

LitVar

Other links and lift over

dbSNP: rs2252576; hg19: chr21-42615293; COSMIC: COSV57740195; COSMIC: COSV57740195;