NM_012104.6:c.786G>C

Variant names:

• chr11-117293108-C-G
• rs638405
• NM_012104.6:c.786G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_012104.6(BACE1):​c.786G>C​(p.Val262Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 1,612,664 control chromosomes in the GnomAD database, including 152,925 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 0.47 (17106 hom., cov: 31)
  • Exomes 𝑓: 0.42 (135819 hom.)
• Consequence: BACE1 NM_012104.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420
• Publications: 48 publications found

Genes affected

BACE1 (HGNC:933): (beta-secretase 1) This gene encodes a member of the peptidase A1 family of aspartic proteases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protease. This transmembrane protease catalyzes the first step in the formation of amyloid beta peptide from amyloid precursor protein. Amyloid beta peptides are the main constituent of amyloid beta plaques, which accumulate in the brains of human Alzheimer's disease patients. [provided by RefSeq, Nov 2015]

BACE1-AS (HGNC:37125): (BACE1 antisense RNA) This gene encodes an unspliced long non-coding RNA transcribed from the opposite strand to BACE1. The encoded transcript is thought to form an RNA duplex with BACE1 mRNA thereby regulating its expression and is also thought to promote post-transcriptional feed-forward regulation of BACE1. This may lead to increased levels of beta amyloid and increased senile plaque deposition, and therefore may play a role in the pathophysiology of Alzheimer's disease. [provided by RefSeq, Jan 2015]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.017).
• BP7: Synonymous conserved (PhyloP=0.042 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012104.6. 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
	BACE1	NM_012104.6	MANE Select	c.786G>C	p.Val262Val	synonymous	Exon 5 of 9	NP_036236.1	P56817-1
	BACE1	NM_138972.4		c.711G>C	p.Val237Val	synonymous	Exon 5 of 9	NP_620428.1	P56817-2
	BACE1	NM_138971.4		c.654G>C	p.Val218Val	synonymous	Exon 5 of 9	NP_620427.1	P56817-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BACE1	ENST00000313005.11	TSL:1 MANE Select	c.786G>C	p.Val262Val	synonymous	Exon 5 of 9	ENSP00000318585.6	P56817-1
	BACE1	ENST00000513780.5	TSL:1	c.711G>C	p.Val237Val	synonymous	Exon 5 of 9	ENSP00000424536.1	P56817-2
	BACE1	ENST00000445823.6	TSL:1	c.654G>C	p.Val218Val	synonymous	Exon 5 of 9	ENSP00000403685.2	P56817-3

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70950 AN: 151782 Hom.: 17088 Cov.: 31

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.481

GnomAD2 exomes AF: 0.487 AC: 122134 AN: 251006 AF XY: 0.484

Gnomad AFR exome AF: 0.526

Gnomad AMR exome AF: 0.629

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.660

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.392

Gnomad OTH exome AF: 0.471

GnomAD4 exome AF: 0.423 AC: 617791 AN: 1460764 Hom.: 135819 Cov.: 41 AF XY: 0.427 AC XY: 310616 AN XY: 726670

African (AFR) AF: 0.527 AC: 17598 AN: 33424

American (AMR) AF: 0.619 AC: 27639 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 11608 AN: 26092

East Asian (EAS) AF: 0.670 AC: 26581 AN: 39654

South Asian (SAS) AF: 0.595 AC: 51297 AN: 86184

European-Finnish (FIN) AF: 0.441 AC: 23551 AN: 53388

Middle Eastern (MID) AF: 0.542 AC: 3128 AN: 5766

European-Non Finnish (NFE) AF: 0.386 AC: 429240 AN: 1111238

Other (OTH) AF: 0.450 AC: 27149 AN: 60354

GnomAD4 genome AF: 0.467 AC: 71001 AN: 151900 Hom.: 17106 Cov.: 31 AF XY: 0.476 AC XY: 35323 AN XY: 74218

African (AFR) AF: 0.521 AC: 21574 AN: 41374

American (AMR) AF: 0.564 AC: 8619 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1552 AN: 3468

East Asian (EAS) AF: 0.662 AC: 3415 AN: 5160

South Asian (SAS) AF: 0.613 AC: 2950 AN: 4816

European-Finnish (FIN) AF: 0.449 AC: 4726 AN: 10536

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.390 AC: 26516 AN: 67956

Other (OTH) AF: 0.483 AC: 1020 AN: 2110

Alfa AF: 0.417 Hom.: 4330

Bravo AF: 0.476

Asia WGS AF: 0.646 AC: 2249 AN: 3478

EpiCase AF: 0.397

EpiControl AF: 0.406

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.65
PhyloP100		0.042
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: rs638405; hg19: chr11-117163824; COSMIC: COSV57284843; COSMIC: COSV57284843;