Genetic Variant LRP8:p.Gly419Gly (chr1-53266643-G-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_004631.5(LRP8):c.1257C>A(p.Gly419Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,612,990 control chromosomes in the GnomAD database, including 131,104 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 0.36 ( 10586 hom., cov: 32)

Exomes 𝑓: 0.40 ( 120518 hom. )

Consequence

LRP8
NM_004631.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.876

Variant links:

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]

LRP8 links:

LOC105378728 (HGNC:):

LOC105378728 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP7

Synonymous conserved (PhyloP=0.876 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP8	NM_004631.5 link	c.1257C>A	p.Gly419Gly	synonymous_variant	Exon 9 of 19	ENST00000306052.12	NP_004622.2	Q14114-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12 link	c.1257C>A	p.Gly419Gly	synonymous_variant	Exon 9 of 19	1	NM_004631.5	ENSP00000303634.6		Q14114-1

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54273

AN:

151848

Hom.:

10584

Cov.:

show subpopulations

Gnomad AFR

AF:

0.229

Gnomad AMI

AF:

0.500

Gnomad AMR

AF:

0.359

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.629

Gnomad SAS

AF:

0.211

Gnomad FIN

AF:

0.441

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.414

Gnomad OTH

AF:

0.319

GnomAD3 exomes

AF:

0.382

AC:

96107

AN:

251266

Hom.:

20067

AF XY:

0.374

AC XY:

50727

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.225

Gnomad AMR exome

AF:

0.373

Gnomad ASJ exome

AF:

0.326

Gnomad EAS exome

AF:

0.643

Gnomad SAS exome

AF:

0.194

Gnomad FIN exome

AF:

0.442

Gnomad NFE exome

AF:

0.411

Gnomad OTH exome

AF:

0.369

GnomAD4 exome

AF:

0.398

AC:

581475

AN:

1461024

Hom.:

120518

Cov.:

AF XY:

0.392

AC XY:

285127

AN XY:

726852

show subpopulations

Gnomad4 AFR exome

AF:

0.225

Gnomad4 AMR exome

AF:

0.363

Gnomad4 ASJ exome

AF:

0.323

Gnomad4 EAS exome

AF:

0.645

Gnomad4 SAS exome

AF:

0.200

Gnomad4 FIN exome

AF:

0.440

Gnomad4 NFE exome

AF:

0.413

Gnomad4 OTH exome

AF:

0.374

GnomAD4 genome

AF:

0.357

AC:

54298

AN:

151966

Hom.:

10586

Cov.:

AF XY:

0.356

AC XY:

26476

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.229

Gnomad4 AMR

AF:

0.359

Gnomad4 ASJ

AF:

0.323

Gnomad4 EAS

AF:

0.629

Gnomad4 SAS

AF:

0.210

Gnomad4 FIN

AF:

0.441

Gnomad4 NFE

AF:

0.414

Gnomad4 OTH

AF:

0.323

Alfa

AF:

0.385

Hom.:

19537

Bravo

AF:

0.350

Asia WGS

AF:

0.380

AC:

1321

AN:

3478

EpiCase

AF:

0.388

EpiControl

AF:

0.387

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.5

DANN

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over