rs4818219

Positions:

• chr21-41175967-A-G
• chr21-41175967-A-T
• chr21-41175967-A-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+7392A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 152,008 control chromosomes in the GnomAD database, including 5,666 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 0.27 (5666 hom., cov: 32)
  • Exomes 𝑓: 0.083 (0 hom.)
• Consequence: BACE2 NM_012105.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.407

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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BACE2	NM_012105.5	c.312+7392A>G		intron_variant		ENST00000330333.11
PLAC4	NR_148920.1	n.9273T>C		non_coding_transcript_exon_variant	1/1
BACE2	NM_138991.3	c.312+7392A>G		intron_variant
BACE2	NM_138992.3	c.312+7392A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACE2	ENST00000330333.11	c.312+7392A>G		intron_variant		1	NM_012105.5	P1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40791 AN: 151878 Hom.: 5658 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.288

GnomAD4 exome AF: 0.0833 AC: 1 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.100 AC XY: 1 AN XY: 10

Gnomad4 AFR exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.269 AC: 40849 AN: 151996 Hom.: 5666 Cov.: 32 AF XY: 0.271 AC XY: 20130 AN XY: 74286

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.374

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.328

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.288

Alfa AF: 0.277 Hom.: 7979

Bravo AF: 0.271

Asia WGS AF: 0.267 AC: 926 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.35
DANN	Benign	0.48

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: rs4818219; hg19: chr21-42547894;