21-41256042-G-A

Variant names:

• chr21-41256042-G-A
• rs11702001
• NM_012105.5:c.1135-1116G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012105.5(BACE2):​c.1135-1116G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 151,608 control chromosomes in the GnomAD database, including 6,909 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6909 hom., cov: 32)
• Consequence: BACE2 NM_012105.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BACE2	NM_012105.5	c.1135-1116G>A		intron_variant	Intron 7 of 8	ENST00000330333.11	NP_036237.2
BACE2	NM_138991.3	c.985-1116G>A		intron_variant	Intron 6 of 7		NP_620476.1
BACE2	NM_138992.3	c.1134+5141G>A		intron_variant	Intron 7 of 7		NP_620477.1
BACE2	XM_017028314.2	c.850-1116G>A		intron_variant	Intron 8 of 9		XP_016883803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BACE2	ENST00000330333.11	c.1135-1116G>A		intron_variant	Intron 7 of 8	1	NM_012105.5	ENSP00000332979.6

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41391 AN: 151492 Hom.: 6881 Cov.: 32

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.254

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.274 AC: 41486 AN: 151608 Hom.: 6909 Cov.: 32 AF XY: 0.271 AC XY: 20093 AN XY: 74064

African (AFR) AF: 0.475 AC: 19609 AN: 41306

American (AMR) AF: 0.241 AC: 3666 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 758 AN: 3464

East Asian (EAS) AF: 0.151 AC: 780 AN: 5170

South Asian (SAS) AF: 0.258 AC: 1234 AN: 4786

European-Finnish (FIN) AF: 0.144 AC: 1498 AN: 10410

Middle Eastern (MID) AF: 0.250 AC: 73 AN: 292

European-Non Finnish (NFE) AF: 0.194 AC: 13210 AN: 67928

Other (OTH) AF: 0.257 AC: 540 AN: 2104

Alfa AF: 0.220 Hom.: 4866

Bravo AF: 0.286

Asia WGS AF: 0.250 AC: 874 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.9
DANN	Benign	0.45
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11702001; hg19: chr21-42627969;