rs2242340

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002335.4(LRP5):c.4586+118C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0916 in 907,300 control chromosomes in the GnomAD database, including 4,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 613 hom., cov: 32)

Exomes 𝑓: 0.093 ( 3612 hom. )

Consequence

LRP5
NM_002335.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.94

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 11-68446651-C-T is Benign according to our data. Variant chr11-68446651-C-T is described in ClinVar as Benign. ClinVar VariationId is 1175466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 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.4586+118C>T		intron	N/A	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.2843+118C>T		intron	N/A	NP_001278831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LRP5	ENST00000294304.12	TSL:1 MANE Select	c.4586+118C>T	intron	N/A	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.*3192+118C>T	intron	N/A	ENSP00000436652.1	E9PHY1
LRP5	ENST00000909991.1		c.4649+118C>T	intron	N/A	ENSP00000580050.1

Frequencies

GnomAD3 genomes

AF:

0.0837

AC:

12724

AN:

152078

Hom.:

613

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0493

Gnomad AMI

AF:

0.247

Gnomad AMR

AF:

0.0814

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.0199

Gnomad SAS

AF:

0.0462

Gnomad FIN

AF:

0.0871

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.108

GnomAD4 exome

AF:

0.0932

AC:

70382

AN:

755104

Hom.:

3612

AF XY:

0.0915

AC XY:

36291

AN XY:

396720

show subpopulations

African (AFR)

AF:

0.0505

AC:

997

AN:

19760

American (AMR)

AF:

0.0693

AC:

2478

AN:

35732

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

2306

AN:

21162

East Asian (EAS)

AF:

0.0285

AC:

957

AN:

33574

South Asian (SAS)

AF:

0.0449

AC:

3055

AN:

68036

European-Finnish (FIN)

AF:

0.0879

AC:

3185

AN:

36226

Middle Eastern (MID)

AF:

0.152

AC:

672

AN:

4416

European-Non Finnish (NFE)

AF:

0.106

AC:

53032

AN:

498908

Other (OTH)

AF:

0.0992

AC:

3700

AN:

37290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

3344

6688

10031

13375

16719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1050

2100

3150

4200

5250

<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:

0.0836

AC:

12725

AN:

152196

Hom.:

613

Cov.:

AF XY:

0.0814

AC XY:

6057

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0493

AC:

2046

AN:

41540

American (AMR)

AF:

0.0813

AC:

1244

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

384

AN:

3470

East Asian (EAS)

AF:

0.0200

AC:

103

AN:

5160

South Asian (SAS)

AF:

0.0460

AC:

222

AN:

4824

European-Finnish (FIN)

AF:

0.0871

AC:

923

AN:

10600

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.107

AC:

7307

AN:

67988

Other (OTH)

AF:

0.106

AC:

224

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

584

1168

1751

2335

2919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<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:

0.0925

Hom.:

Bravo

AF:

0.0840

Asia WGS

AF:

0.0500

AC:

175

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.7

(source)

DANN

Benign

0.66

PhyloP100

-1.9

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over