11-68312746-CGCTGCTGCT-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_002335.4(LRP5):c.52_60delCTGCTGCTG(p.Leu18_Leu20del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,061,146 control chromosomes in the GnomAD database, including 75 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L18L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0090 ( 5 hom., cov: 28)

Exomes 𝑓: 0.014 ( 70 hom. )

Consequence

LRP5
NM_002335.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 0.190

Publications

4 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
exudative vitreoretinopathy 4
Inheritance: AD, SD, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
inherited retinal dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
osteoporosis-pseudoglioma syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal dominant osteosclerosis, Worth type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
polycystic liver disease 4 with or without kidney cysts
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal dominant osteopetrosis 1
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
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 -16 ACMG points.

BP6

Variant 11-68312746-CGCTGCTGCT-C is Benign according to our data. Variant chr11-68312746-CGCTGCTGCT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 204504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00902 (1303/144404) while in subpopulation NFE AF = 0.0137 (894/65172). AF 95% confidence interval is 0.013. There are 5 homozygotes in GnomAd4. There are 584 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR,SD,Unknown gene

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.52_60delCTGCTGCTG	p.Leu18_Leu20del	conservative_inframe_deletion	Exon 1 of 23	NP_002326.2
	LRP5	NM_001291902.2		c.-1714_-1706delCTGCTGCTG		5_prime_UTR	Exon 1 of 23	NP_001278831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LRP5	ENST00000294304.12	TSL:1 MANE Select	c.52_60delCTGCTGCTG	p.Leu18_Leu20del	conservative_inframe_deletion	Exon 1 of 23	ENSP00000294304.6
LRP5	ENST00000529993.5	TSL:1	n.52_60delCTGCTGCTG		non_coding_transcript_exon	Exon 1 of 23	ENSP00000436652.1
LRP5	ENST00000909991.1		c.52_60delCTGCTGCTG	p.Leu18_Leu20del	conservative_inframe_deletion	Exon 1 of 23	ENSP00000580050.1

Frequencies

GnomAD3 genomes

AF:

0.00901

AC:

1300

AN:

144318

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00371

Gnomad AMI

AF:

0.00340

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00446

Gnomad EAS

AF:

0.000809

Gnomad SAS

AF:

0.00168

Gnomad FIN

AF:

0.00383

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.00901

GnomAD2 exomes

AF:

0.000491

AC:

AN:

16308

AF XY:

0.000812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000681

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0137

AC:

12529

AN:

916742

Hom.:

AF XY:

0.0134

AC XY:

5870

AN XY:

438388

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

17012

American (AMR)

AF:

0.00361

AC:

AN:

6652

Ashkenazi Jewish (ASJ)

AF:

0.00332

AC:

AN:

8138

East Asian (EAS)

AF:

0.000171

AC:

AN:

5838

South Asian (SAS)

AF:

0.00135

AC:

AN:

28820

European-Finnish (FIN)

AF:

0.00341

AC:

AN:

5864

Middle Eastern (MID)

AF:

0.00254

AC:

AN:

1966

European-Non Finnish (NFE)

AF:

0.0149

AC:

12071

AN:

811196

Other (OTH)

AF:

0.00979

AC:

306

AN:

31256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

680

1359

2039

2718

3398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

600

1200

1800

2400

3000

<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:

0.00902

AC:

1303

AN:

144404

Hom.:

Cov.:

AF XY:

0.00831

AC XY:

584

AN XY:

70312

show subpopulations

African (AFR)

AF:

0.00377

AC:

151

AN:

40016

American (AMR)

AF:

0.0121

AC:

178

AN:

14652

Ashkenazi Jewish (ASJ)

AF:

0.00446

AC:

AN:

3366

East Asian (EAS)

AF:

0.000812

AC:

AN:

4926

South Asian (SAS)

AF:

0.00169

AC:

AN:

4736

European-Finnish (FIN)

AF:

0.00383

AC:

AN:

8356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0137

AC:

894

AN:

65172

Other (OTH)

AF:

0.00893

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

118

176

235

294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00676

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Autosomal dominant polycystic liver disease (1)

Increased bone mineral density (1)

Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.19

Mutation Taster

=185/15

polymorphism

(source)

Splicing

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