NM_002335.4:c.55_60dupCTGCTG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_002335.4(LRP5):c.55_60dupCTGCTG(p.Leu19_Leu20dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000929 in 1,061,312 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A21A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 28)

Exomes 𝑓: 0.00088 ( 2 hom. )

Consequence

LRP5
NM_002335.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 0.00

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 -9 ACMG points.

BP6

Variant 11-68312746-C-CGCTGCT is Benign according to our data. Variant chr11-68312746-C-CGCTGCT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372405.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00125 (181/144416) while in subpopulation EAS AF = 0.00974 (48/4926). AF 95% confidence interval is 0.00755. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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.55_60dupCTGCTG	p.Leu19_Leu20dup	conservative_inframe_insertion	Exon 1 of 23	NP_002326.2
	LRP5	NM_001291902.2		c.-1711_-1706dupCTGCTG		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.55_60dupCTGCTG	p.Leu19_Leu20dup	conservative_inframe_insertion	Exon 1 of 23	ENSP00000294304.6
LRP5	ENST00000529993.5	TSL:1	n.55_60dupCTGCTG		non_coding_transcript_exon	Exon 1 of 23	ENSP00000436652.1
LRP5	ENST00000909991.1		c.55_60dupCTGCTG	p.Leu19_Leu20dup	conservative_inframe_insertion	Exon 1 of 23	ENSP00000580050.1

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

182

AN:

144330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000902

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000888

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0101

Gnomad SAS

AF:

0.00189

Gnomad FIN

AF:

0.000120

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00100

GnomAD2 exomes

AF:

0.000491

AC:

AN:

16308

AF XY:

0.000507

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000349

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000878

AC:

805

AN:

916896

Hom.:

Cov.:

AF XY:

0.000892

AC XY:

391

AN XY:

438478

show subpopulations

African (AFR)

AF:

0.000705

AC:

AN:

17010

American (AMR)

AF:

0.00241

AC:

AN:

6650

Ashkenazi Jewish (ASJ)

AF:

0.000246

AC:

AN:

8138

East Asian (EAS)

AF:

0.00736

AC:

AN:

5840

South Asian (SAS)

AF:

0.000728

AC:

AN:

28828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1966

European-Non Finnish (NFE)

AF:

0.000805

AC:

653

AN:

811330

Other (OTH)

AF:

0.00186

AC:

AN:

31264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<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:

0.00125

AC:

181

AN:

144416

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

70312

show subpopulations

African (AFR)

AF:

0.000900

AC:

AN:

40018

American (AMR)

AF:

0.000955

AC:

AN:

14654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3366

East Asian (EAS)

AF:

0.00974

AC:

AN:

4926

South Asian (SAS)

AF:

0.00190

AC:

AN:

4736

European-Finnish (FIN)

AF:

0.000120

AC:

AN:

8356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

65180

Other (OTH)

AF:

0.000992

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000313

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

LRP5-related disorder (1)

not specified (1)

Osteogenesis imperfecta (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=74/26

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