21-26173869-C-G

Variant names:

• chr21-26173869-C-G
• rs463946
• ENST00000455275.1:n.178-1741C>G

Variant summary

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

The ENST00000455275.1(ENSG00000224541):​n.178-1741C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0853 in 152,248 control chromosomes in the GnomAD database, including 1,005 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 0.085 (1005 hom., cov: 33)
• Consequence: ENSG00000224541 ENST00000455275.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0670
• Publications: 10 publications found

Genes affected

ENSG00000224541 (HGNC:):

APP-DT (HGNC:55075): (APP divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000455275.1. 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
	APP-DT	NR_186395.1		n.186+2817C>G		intron	N/A
	APP-DT	NR_186396.1		n.186+2817C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000224541	ENST00000455275.1	TSL:2	n.178-1741C>G		intron	N/A
	APP-DT	ENST00000608591.5	TSL:4	n.182+2817C>G		intron	N/A
	APP-DT	ENST00000609365.2	TSL:4	n.172+2817C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0852 AC: 12958 AN: 152128 Hom.: 999 Cov.: 33

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0693

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.0775

Gnomad FIN AF: 0.0653

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0751

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

GnomAD4 genome AF: 0.0853 AC: 12988 AN: 152248 Hom.: 1005 Cov.: 33 AF XY: 0.0868 AC XY: 6464 AN XY: 74438

African (AFR) AF: 0.193 AC: 7998 AN: 41518

American (AMR) AF: 0.0699 AC: 1070 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.203 AC: 1052 AN: 5176

South Asian (SAS) AF: 0.0769 AC: 371 AN: 4822

European-Finnish (FIN) AF: 0.0653 AC: 693 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1630 AN: 68038

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0182 Hom.: 7

Bravo AF: 0.0915

Asia WGS AF: 0.147 AC: 510 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.4
DANN	Benign	0.80
PhyloP100		0.067
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs463946; hg19: chr21-27546187;