21-41186767-T-C

Position:

• chr21-41186767-T-C

Variant summary

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

The NM_012105.5(BACE2):​c.312+18192T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0398 in 152,364 control chromosomes in the GnomAD database, including 205 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 0.040 (205 hom., cov: 33)
  • Exomes 𝑓: 0.056 (0 hom.)
• Consequence: BACE2 NM_012105.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.289

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]

PLAC4 (HGNC:14616): (placenta enriched 4)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BACE2	NM_012105.5	c.312+18192T>C		intron_variant		ENST00000330333.11
BACE2	NM_138991.3	c.312+18192T>C		intron_variant
BACE2	NM_138992.3	c.312+18192T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACE2	ENST00000330333.11	c.312+18192T>C		intron_variant		1	NM_012105.5	P1
PLAC4	ENST00000430327.6	n.7A>G		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6050 AN: 152210 Hom.: 205 Cov.: 33

Gnomad AFR AF: 0.0896

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0405

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0354

GnomAD4 exome AF: 0.0556 AC: 2 AN: 36 Hom.: 0 Cov.: 0 AF XY: 0.0833 AC XY: 2 AN XY: 24

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0333

GnomAD4 genome AF: 0.0398 AC: 6062 AN: 152328 Hom.: 205 Cov.: 33 AF XY: 0.0401 AC XY: 2989 AN XY: 74488

Gnomad4 AFR AF: 0.0897

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0402

Gnomad4 FIN AF: 0.0241

Gnomad4 NFE AF: 0.0202

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0239 Hom.: 60

Bravo AF: 0.0406

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.9
DANN	Benign	0.85

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: rs9981478; hg19: chr21-42558694;