21-41243366-C-T

Variant names:

• chr21-41243366-C-T
• rs2252576
• NM_012105.5:c.748-10C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_012105.5(BACE2):​c.748-10C>T variant causes a 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.36 (13983 hom., cov: 32)
  • Exomes 𝑓: 0.24 (47177 hom.)
• Consequence: BACE2 NM_012105.5 intron
• Scores: Splicing: ADA: 0.00001374
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.359
• Publications: 24 publications found

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

Our verdict: Benign. The variant received -13 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 CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-41243366-C-T is described in CliVar as Benign. Clinvar id is 3059580.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
BACE2	NM_012105.5	c.748-10C>T		intron_variant	Intron 4 of 8	ENST00000330333.11	NP_036237.2
BACE2	NM_138991.3	c.748-10C>T		intron_variant	Intron 4 of 7		NP_620476.1
BACE2	NM_138992.3	c.748-10C>T		intron_variant	Intron 4 of 7		NP_620477.1
BACE2	XM_017028314.2	c.463-10C>T		intron_variant	Intron 5 of 9		XP_016883803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BACE2	ENST00000330333.11	c.748-10C>T		intron_variant	Intron 4 of 8	1	NM_012105.5	ENSP00000332979.6

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

GnomAD2 exomes AF: 0.235 AC: 54424 AN: 231610 AF XY: 0.228

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 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

African (AFR) AF: 0.743 AC: 23830 AN: 32062

American (AMR) AF: 0.155 AC: 6238 AN: 40300

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 6985 AN: 25058

East Asian (EAS) AF: 0.0712 AC: 2774 AN: 38934

South Asian (SAS) AF: 0.183 AC: 14403 AN: 78764

European-Finnish (FIN) AF: 0.197 AC: 10429 AN: 52876

Middle Eastern (MID) AF: 0.240 AC: 1353 AN: 5640

European-Non Finnish (NFE) AF: 0.240 AC: 262809 AN: 1093886

Other (OTH) AF: 0.257 AC: 15151 AN: 58932

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

African (AFR) AF: 0.722 AC: 29919 AN: 41428

American (AMR) AF: 0.254 AC: 3877 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 961 AN: 3472

East Asian (EAS) AF: 0.0720 AC: 372 AN: 5170

South Asian (SAS) AF: 0.193 AC: 928 AN: 4816

European-Finnish (FIN) AF: 0.190 AC: 2007 AN: 10560

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16108 AN: 67952

Other (OTH) AF: 0.338 AC: 712 AN: 2106

Alfa AF: 0.280 Hom.: 13789

Bravo AF: 0.381

Asia WGS AF: 0.173 AC: 604 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BACE2-related disorder Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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