21-41275894-C-T

Variant names:

• chr21-41275894-C-T
• rs12149
• NM_012105.5:c.*270C>T

Variant summary

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

The NM_012105.5(BACE2):​c.*270C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 445,950 control chromosomes in the GnomAD database, including 53,799 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 0.41 (14998 hom., cov: 32)
  • Exomes 𝑓: 0.50 (38801 hom.)
• Consequence: BACE2 NM_012105.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.845
• Publications: 17 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.678 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.*270C>T		3_prime_UTR	Exon 9 of 9	NP_036237.2
	BACE2	NM_138991.3		c.*270C>T		3_prime_UTR	Exon 8 of 8	NP_620476.1	Q9Y5Z0-2
	BACE2	NM_138992.3		c.*467C>T		3_prime_UTR	Exon 8 of 8	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.*270C>T		3_prime_UTR	Exon 9 of 9	ENSP00000332979.6	Q9Y5Z0-1
	BACE2	ENST00000347667.5	TSL:1	c.*270C>T		3_prime_UTR	Exon 8 of 8	ENSP00000327528.4	Q9Y5Z0-2
	BACE2	ENST00000328735.10	TSL:1	c.*467C>T		3_prime_UTR	Exon 8 of 8	ENSP00000333854.6	Q9Y5Z0-3

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62575 AN: 151884 Hom.: 14996 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.437

GnomAD4 exome AF: 0.503 AC: 147733 AN: 293948 Hom.: 38801 Cov.: 4 AF XY: 0.507 AC XY: 76978 AN XY: 151882

African (AFR) AF: 0.162 AC: 1579 AN: 9744

American (AMR) AF: 0.591 AC: 7007 AN: 11848

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 4453 AN: 9750

East Asian (EAS) AF: 0.687 AC: 14059 AN: 20468

South Asian (SAS) AF: 0.548 AC: 14000 AN: 25536

European-Finnish (FIN) AF: 0.450 AC: 7346 AN: 16308

Middle Eastern (MID) AF: 0.504 AC: 689 AN: 1368

European-Non Finnish (NFE) AF: 0.497 AC: 90075 AN: 181246

Other (OTH) AF: 0.482 AC: 8525 AN: 17680

GnomAD4 genome AF: 0.412 AC: 62582 AN: 152002 Hom.: 14998 Cov.: 32 AF XY: 0.417 AC XY: 31000 AN XY: 74278

African (AFR) AF: 0.159 AC: 6606 AN: 41466

American (AMR) AF: 0.546 AC: 8345 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1586 AN: 3468

East Asian (EAS) AF: 0.697 AC: 3591 AN: 5152

South Asian (SAS) AF: 0.544 AC: 2623 AN: 4818

European-Finnish (FIN) AF: 0.448 AC: 4721 AN: 10546

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.495 AC: 33604 AN: 67946

Other (OTH) AF: 0.439 AC: 928 AN: 2114

Alfa AF: 0.472 Hom.: 68058

Bravo AF: 0.411

Asia WGS AF: 0.563 AC: 1956 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.48
PhyloP100		0.84
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: rs12149; hg19: chr21-42647821;