Genetic Variant LRP8:p.Gly419Gly (chr1-53266643-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP7BA1

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

Publications

39 publications found

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 Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

LRP8 links:

LOC105378728 (HGNC:):

LOC105378728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.259).

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

GnomAD2 exomes

AF:

0.382

AC:

96107

AN:

251266

AF XY:

0.374

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 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

African (AFR)

AF:

0.225

AC:

7524

AN:

33460

American (AMR)

AF:

0.363

AC:

16244

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

8449

AN:

26118

East Asian (EAS)

AF:

0.645

AC:

25609

AN:

39694

South Asian (SAS)

AF:

0.200

AC:

17268

AN:

86230

European-Finnish (FIN)

AF:

0.440

AC:

23486

AN:

53396

Middle Eastern (MID)

AF:

0.244

AC:

1395

AN:

5718

European-Non Finnish (NFE)

AF:

0.413

AC:

458927

AN:

1111354

Other (OTH)

AF:

0.374

AC:

22573

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

16277

32554

48831

65108

81385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14032

28064

42096

56128

70160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.357

AC:

54298

AN:

151966

Hom.:

10586

Cov.:

AF XY:

0.356

AC XY:

26476

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.229

AC:

9477

AN:

41470

American (AMR)

AF:

0.359

AC:

5476

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1122

AN:

3472

East Asian (EAS)

AF:

0.629

AC:

3242

AN:

5156

South Asian (SAS)

AF:

0.210

AC:

1013

AN:

4816

European-Finnish (FIN)

AF:

0.441

AC:

4653

AN:

10552

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.414

AC:

28116

AN:

67938

Other (OTH)

AF:

0.323

AC:

680

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1734

3468

5203

6937

8671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

528

1056

1584

2112

2640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.383

Hom.:

24789

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

(source)

DANN

Benign

0.86

PhyloP100

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=289/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over