chr21-41248222-G-A

Variant names:

• chr21-41248222-G-A
• rs2837990
• NM_012105.5:c.984+2159G>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.984+2159G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,096 control chromosomes in the GnomAD database, including 5,269 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 0.25 (5269 hom., cov: 32)
• Consequence: BACE2 NM_012105.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65
• Publications: 10 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012105.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BACE2	NM_012105.5	MANE Select	c.984+2159G>A		intron	N/A	NP_036237.2
	BACE2	NM_138991.3		c.984+2159G>A		intron	N/A	NP_620476.1	Q9Y5Z0-2
	BACE2	NM_138992.3		c.984+2159G>A		intron	N/A	NP_620477.1	Q9Y5Z0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BACE2	ENST00000330333.11	TSL:1 MANE Select	c.984+2159G>A		intron	N/A	ENSP00000332979.6	Q9Y5Z0-1
	BACE2	ENST00000347667.5	TSL:1	c.984+2159G>A		intron	N/A	ENSP00000327528.4	Q9Y5Z0-2
	BACE2	ENST00000328735.10	TSL:1	c.984+2159G>A		intron	N/A	ENSP00000333854.6	Q9Y5Z0-3

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37585 AN: 151978 Hom.: 5259 Cov.: 32

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.243

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

GnomAD4 genome AF: 0.248 AC: 37648 AN: 152096 Hom.: 5269 Cov.: 32 AF XY: 0.246 AC XY: 18255 AN XY: 74340

African (AFR) AF: 0.387 AC: 16040 AN: 41456

American (AMR) AF: 0.241 AC: 3693 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3472

East Asian (EAS) AF: 0.179 AC: 923 AN: 5160

South Asian (SAS) AF: 0.257 AC: 1239 AN: 4812

European-Finnish (FIN) AF: 0.142 AC: 1509 AN: 10602

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.187 AC: 12710 AN: 67978

Other (OTH) AF: 0.245 AC: 518 AN: 2114

Alfa AF: 0.211 Hom.: 11734

Bravo AF: 0.258

Asia WGS AF: 0.241 AC: 842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.31
DANN	Benign	0.67
PhyloP100		-1.6
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: rs2837990; hg19: chr21-42620149;