Variant chr1-53250744-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000306052.12(LRP8):c.2622C>A(p.Asp874Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

LRP8
ENST00000306052.12 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.466

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:

LRP8 (HGNC:):

LRP8 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10224545).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP8	NM_004631.5 linkuse as main transcript	c.2622C>A	p.Asp874Glu	missense_variant	17/19	ENST00000306052.12	NP_004622.2	Q14114-1
LRP8	NM_001018054.3 linkuse as main transcript	c.2622C>A	p.Asp874Glu	missense_variant	17/18		NP_001018064.1	Q14114-3
LRP8	NM_033300.4 linkuse as main transcript	c.2112C>A	p.Asp704Glu	missense_variant	15/17		NP_150643.2	Q14114-4
LRP8	NM_017522.5 linkuse as main transcript	c.2010C>A	p.Asp670Glu	missense_variant	15/16		NP_059992.3	Q14114-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12 linkuse as main transcript	c.2622C>A	p.Asp874Glu	missense_variant	17/19	1	NM_004631.5	ENSP00000303634.6		Q14114-1

Frequencies

GnomAD3 genomes

AF:

0.0000593

AC:

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251392

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000593

AC:

AN:

151892

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74168

show subpopulations

Gnomad4 AFR

AF:

0.000218

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.54

CADD

Benign

2.3

DANN

Uncertain

0.98

DEOGEN2

Benign

0.072

T;.;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.80

T;T;.;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.10

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

L;L;.;.;.

MutationTaster

Benign

0.97

P;P;P;P;P

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.67

N;N;N;N;N

REVEL

Benign

0.040

Sift

Benign

0.45

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.011

B;B;B;B;B

Vest4

0.16

MutPred

0.23

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;.;.;

MVP

0.68

MPC

0.37

ClinPred

0.022

GERP RS

-2.6

Varity_R

0.027

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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