21-41270111-A-G

Position:

• chr21-41270111-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012105.5(BACE2):​c.1304-5260A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 152,032 control chromosomes in the GnomAD database, including 37,016 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 0.69 (37016 hom., cov: 32)
• Consequence: BACE2 NM_012105.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.577

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BACE2	NM_012105.5	c.1304-5260A>G		intron_variant		ENST00000330333.11	NP_036237.2
BACE2	NM_138991.3	c.1154-5260A>G		intron_variant			NP_620476.1
BACE2	NM_138992.3	c.1135-5260A>G		intron_variant			NP_620477.1
BACE2	XM_017028314.2	c.1019-5260A>G		intron_variant			XP_016883803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BACE2	ENST00000330333.11	c.1304-5260A>G		intron_variant		1	NM_012105.5	ENSP00000332979	P1

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104838 AN: 151914 Hom.: 37007 Cov.: 32

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.837

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.723

Gnomad OTH AF: 0.733

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

GnomAD4 genome AF: 0.690 AC: 104883 AN: 152032 Hom.: 37016 Cov.: 32 AF XY: 0.695 AC XY: 51659 AN XY: 74316

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.796

Gnomad4 ASJ AF: 0.738

Gnomad4 EAS AF: 0.987

Gnomad4 SAS AF: 0.836

Gnomad4 FIN AF: 0.677

Gnomad4 NFE AF: 0.723

Gnomad4 OTH AF: 0.735

Alfa AF: 0.727 Hom.: 79502

Bravo AF: 0.692

Asia WGS AF: 0.897 AC: 3116 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.3
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs8133778; hg19: chr21-42642038;