rs2277268

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002335.4(LRP5):c.1932G>A(p.Glu644Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0671 in 1,614,058 control chromosomes in the GnomAD database, including 3,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 358 hom., cov: 33)

Exomes 𝑓: 0.068 ( 3518 hom. )

Consequence

LRP5
NM_002335.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.629

Publications

32 publications found

Variant links:

Genes affected

LRP5 (HGNC:6697): (LDL receptor related protein 5) This gene encodes a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins and was originally cloned on the basis of its association with type 1 diabetes mellitus in humans. This protein plays a key role in skeletal homeostasis and many bone density related diseases are caused by mutations in this gene. Mutations in this gene also cause familial exudative vitreoretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

LRP5 Gene-Disease associations (from GenCC):

bone mineral density quantitative trait locus 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
LRP5-related exudative vitreoretinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
osteoporosis-pseudoglioma syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
exudative vitreoretinopathy 4
Inheritance: Unknown, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal dominant osteosclerosis, Worth type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
polycystic liver disease 4 with or without kidney cysts
Inheritance: AD Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
autosomal dominant osteopetrosis 1
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
exudative vitreoretinopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hyperostosis corticalis generalisata
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteosclerosis-developmental delay-craniosynostosis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
polycystic liver disease 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LRP5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 11-68406654-G-A is Benign according to our data. Variant chr11-68406654-G-A is described in ClinVar as Benign. ClinVar VariationId is 258635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.629 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002335.4. 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
	LRP5	NM_002335.4	MANE Select	c.1932G>A	p.Glu644Glu	synonymous	Exon 9 of 23	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.189G>A	p.Glu63Glu	synonymous	Exon 9 of 23	NP_001278831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRP5	ENST00000294304.12	TSL:1 MANE Select	c.1932G>A	p.Glu644Glu	synonymous	Exon 9 of 23	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.*538G>A		non_coding_transcript_exon	Exon 9 of 23	ENSP00000436652.1	E9PHY1
LRP5	ENST00000529993.5	TSL:1	n.*538G>A		3_prime_UTR	Exon 9 of 23	ENSP00000436652.1	E9PHY1

Frequencies

GnomAD3 genomes

AF:

0.0630

AC:

9590

AN:

152118

Hom.:

357

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0637

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0581

Gnomad ASJ

AF:

0.0495

Gnomad EAS

AF:

0.0439

Gnomad SAS

AF:

0.0408

Gnomad FIN

AF:

0.0449

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.0701

Gnomad OTH

AF:

0.0676

GnomAD2 exomes

AF:

0.0583

AC:

14656

AN:

251324

AF XY:

0.0585

show subpopulations

Gnomad AFR exome

AF:

0.0669

Gnomad AMR exome

AF:

0.0446

Gnomad ASJ exome

AF:

0.0488

Gnomad EAS exome

AF:

0.0413

Gnomad FIN exome

AF:

0.0449

Gnomad NFE exome

AF:

0.0724

Gnomad OTH exome

AF:

0.0675

GnomAD4 exome

AF:

0.0675

AC:

98731

AN:

1461822

Hom.:

3518

Cov.:

AF XY:

0.0667

AC XY:

48481

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0664

AC:

2223

AN:

33480

American (AMR)

AF:

0.0464

AC:

2077

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0474

AC:

1240

AN:

26136

East Asian (EAS)

AF:

0.0413

AC:

1640

AN:

39700

South Asian (SAS)

AF:

0.0377

AC:

3251

AN:

86258

European-Finnish (FIN)

AF:

0.0445

AC:

2375

AN:

53384

Middle Eastern (MID)

AF:

0.123

AC:

709

AN:

5768

European-Non Finnish (NFE)

AF:

0.0728

AC:

80977

AN:

1111982

Other (OTH)

AF:

0.0702

AC:

4239

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

5653

11306

16959

22612

28265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2956

5912

8868

11824

14780

<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:

0.0631

AC:

9600

AN:

152236

Hom.:

358

Cov.:

AF XY:

0.0615

AC XY:

4579

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0638

AC:

2649

AN:

41526

American (AMR)

AF:

0.0580

AC:

887

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0495

AC:

172

AN:

3472

East Asian (EAS)

AF:

0.0436

AC:

226

AN:

5180

South Asian (SAS)

AF:

0.0411

AC:

198

AN:

4822

European-Finnish (FIN)

AF:

0.0449

AC:

476

AN:

10594

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0702

AC:

4774

AN:

68028

Other (OTH)

AF:

0.0678

AC:

143

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

459

918

1377

1836

2295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0716

Hom.:

652

Bravo

AF:

0.0662

Asia WGS

AF:

0.0740

AC:

257

AN:

3478

EpiCase

AF:

0.0763

EpiControl

AF:

0.0808

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

8.9

(source)

DANN

Benign

0.60

PhyloP100

0.63

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over