11-68312746-CGCTGCTGCTGCTGCT-CGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr11-68312746-C-CGCTGCT
• rs72555376
• NM_002335.4:c.55_60dupCTGCTG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.00
• Publications: 4 publications found

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

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 1 Cov.: 28

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: 8 AN: 16308 AF XY: 0.000507

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.: 2 Cov.: 5 AF XY: 0.000892 AC XY: 391 AN XY: 438478

African (AFR) AF: 0.000705 AC: 12 AN: 17010

American (AMR) AF: 0.00241 AC: 16 AN: 6650

Ashkenazi Jewish (ASJ) AF: 0.000246 AC: 2 AN: 8138

East Asian (EAS) AF: 0.00736 AC: 43 AN: 5840

South Asian (SAS) AF: 0.000728 AC: 21 AN: 28828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1966

European-Non Finnish (NFE) AF: 0.000805 AC: 653 AN: 811330

Other (OTH) AF: 0.00186 AC: 58 AN: 31264

GnomAD4 genome AF: 0.00125 AC: 181 AN: 144416 Hom.: 1 Cov.: 28 AF XY: 0.00125 AC XY: 88 AN XY: 70312

African (AFR) AF: 0.000900 AC: 36 AN: 40018

American (AMR) AF: 0.000955 AC: 14 AN: 14654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3366

East Asian (EAS) AF: 0.00974 AC: 48 AN: 4926

South Asian (SAS) AF: 0.00190 AC: 9 AN: 4736

European-Finnish (FIN) AF: 0.000120 AC: 1 AN: 8356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00109 AC: 71 AN: 65180

Other (OTH) AF: 0.000992 AC: 2 AN: 2016

Alfa AF: 0.000313 Hom.: 16

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	LRP5-related disorder (1)
-	-	1	not specified (1)
-	-	1	Osteogenesis imperfecta (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=74/26	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs72555376; hg19: chr11-68080214;