rs12039021

chr1-53290007-A-Cchr1-53290007-A-G

Variant summary

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

The NM_004631.5(LRP8):c.245-318T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 151,934 control chromosomes in the GnomAD database, including 10,421 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 0.34 (10421 hom., cov: 32)
• Consequence: LRP8 NM_004631.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.906

Genes affected

LRP8 (HGNC:6700): (LDL receptor related protein 8) This gene encodes a member of the low density lipoprotein receptor (LDLR) family. Low density lipoprotein receptors are cell surface proteins that play roles in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation. The encoded protein plays a critical role in the migration of neurons during development by mediating Reelin signaling, and also functions as a receptor for the cholesterol transport protein apolipoprotein E. Expression of this gene may be a marker for major depressive disorder. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP8	NM_004631.5	c.245-318T>G		intron_variant		ENST00000306052.12
LRP8	NM_001018054.3	c.245-318T>G		intron_variant
LRP8	NM_017522.5	c.245-318T>G		intron_variant
LRP8	NM_033300.4	c.245-318T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP8	ENST00000306052.12	c.245-318T>G		intron_variant		1	NM_004631.5	A2

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52354 AN: 151816 Hom.: 10412 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.340

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

GnomAD4 genome AF: 0.345 AC: 52379 AN: 151934 Hom.: 10421 Cov.: 32 AF XY: 0.346 AC XY: 25708 AN XY: 74246

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.345

Gnomad4 ASJ AF: 0.417

Gnomad4 EAS AF: 0.593

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.455

Gnomad4 NFE AF: 0.423

Gnomad4 OTH AF: 0.344

Alfa AF: 0.401 Hom.: 12022

Bravo AF: 0.328

Asia WGS AF: 0.465 AC: 1615 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.8
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs12039021; hg19: chr1-53755679;