21-41210000-T-C

Position:

• chr21-41210000-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.313-16266T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 151,968 control chromosomes in the GnomAD database, including 65,851 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 0.93 (65851 hom., cov: 29)
• Consequence: BACE2 NM_012105.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BACE2	NM_012105.5	c.313-16266T>C		intron_variant		ENST00000330333.11
BACE2	NM_138991.3	c.313-16266T>C		intron_variant
BACE2	NM_138992.3	c.313-16266T>C		intron_variant
BACE2	XM_017028314.2	c.-483-523T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACE2	ENST00000330333.11	c.313-16266T>C		intron_variant		1	NM_012105.5	P1
BACE2	ENST00000328735.10	c.313-16266T>C		intron_variant		1
BACE2	ENST00000347667.5	c.313-16266T>C		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.928 AC: 140842 AN: 151850 Hom.: 65800 Cov.: 29

Gnomad AFR AF: 0.985

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.753

Gnomad ASJ AF: 0.948

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.873

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.946

Gnomad OTH AF: 0.926

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

GnomAD4 genome AF: 0.927 AC: 140946 AN: 151968 Hom.: 65851 Cov.: 29 AF XY: 0.921 AC XY: 68375 AN XY: 74262

Gnomad4 AFR AF: 0.985

Gnomad4 AMR AF: 0.753

Gnomad4 ASJ AF: 0.948

Gnomad4 EAS AF: 0.801

Gnomad4 SAS AF: 0.956

Gnomad4 FIN AF: 0.873

Gnomad4 NFE AF: 0.946

Gnomad4 OTH AF: 0.920

Alfa AF: 0.936 Hom.: 87290

Bravo AF: 0.915

Asia WGS AF: 0.865 AC: 3010 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.20
DANN	Benign	0.43

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: rs7510366; hg19: chr21-42581927;