chr21-41211811-G-A

Variant names:

• chr21-41211811-G-A
• rs6517656
• NM_012105.5:c.313-14455G>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.313-14455G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 152,208 control chromosomes in the GnomAD database, including 13,572 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 0.33 (13572 hom., cov: 33)
• Consequence: BACE2 NM_012105.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 26 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=-0.67).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BACE2	NM_012105.5	c.313-14455G>A		intron_variant	Intron 1 of 8	ENST00000330333.11	NP_036237.2
BACE2	NM_138991.3	c.313-14455G>A		intron_variant	Intron 1 of 7		NP_620476.1
BACE2	NM_138992.3	c.313-14455G>A		intron_variant	Intron 1 of 7		NP_620477.1
BACE2	XM_017028314.2	c.27+779G>A		intron_variant	Intron 2 of 9		XP_016883803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BACE2	ENST00000330333.11	c.313-14455G>A		intron_variant	Intron 1 of 8	1	NM_012105.5	ENSP00000332979.6
BACE2	ENST00000347667.5	c.313-14455G>A		intron_variant	Intron 1 of 7	1		ENSP00000327528.4
BACE2	ENST00000328735.10	c.313-14455G>A		intron_variant	Intron 1 of 7	1		ENSP00000333854.6

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49746 AN: 152090 Hom.: 13518 Cov.: 33

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.0430

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.328 AC: 49853 AN: 152208 Hom.: 13572 Cov.: 33 AF XY: 0.320 AC XY: 23844 AN XY: 74408

African (AFR) AF: 0.752 AC: 31249 AN: 41532

American (AMR) AF: 0.222 AC: 3387 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 628 AN: 3470

East Asian (EAS) AF: 0.0427 AC: 221 AN: 5174

South Asian (SAS) AF: 0.172 AC: 831 AN: 4824

European-Finnish (FIN) AF: 0.161 AC: 1701 AN: 10598

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10993 AN: 68002

Other (OTH) AF: 0.307 AC: 650 AN: 2116

Alfa AF: 0.217 Hom.: 18164

Bravo AF: 0.349

Asia WGS AF: 0.168 AC: 586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.79
PhyloP100		1.1
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: rs6517656; hg19: chr21-42583738;