11-68312746-C-CGCT

Variant names:

• chr11-68312746-C-CGCT
• rs72555376
• NM_002335.4:c.58_60dupCTG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002335.4(LRP5):​c.58_60dupCTG​(p.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 0.0833 in 1,060,778 control chromosomes in the GnomAD database, including 2,064 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A21A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (821 hom., cov: 28)
  • Exomes 𝑓: 0.080 (1243 hom.)
• Consequence: LRP5 NM_002335.4 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:7
• 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 -16 ACMG points.

• BP6: Variant 11-68312746-C-CGCT is Benign according to our data. Variant chr11-68312746-C-CGCT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 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.58_60dupCTG	p.Leu20dup	conservative_inframe_insertion	Exon 1 of 23	NP_002326.2
	LRP5	NM_001291902.2		c.-1708_-1706dupCTG		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.58_60dupCTG	p.Leu20dup	conservative_inframe_insertion	Exon 1 of 23	ENSP00000294304.6
	LRP5	ENST00000529993.5	TSL:1	n.58_60dupCTG		non_coding_transcript_exon	Exon 1 of 23	ENSP00000436652.1
	LRP5	ENST00000909991.1		c.58_60dupCTG	p.Leu20dup	conservative_inframe_insertion	Exon 1 of 23	ENSP00000580050.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 14633 AN: 144284 Hom.: 819 Cov.: 28

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.0125

Gnomad AMR AF: 0.0696

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0178

Gnomad SAS AF: 0.0729

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.0839

Gnomad OTH AF: 0.0866

GnomAD2 exomes AF: 0.0724 AC: 1181 AN: 16308 AF XY: 0.0727

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.0152

Gnomad FIN exome AF: 0.0984

Gnomad NFE exome AF: 0.0752

Gnomad OTH exome AF: 0.0913

GnomAD4 exome AF: 0.0805 AC: 73751 AN: 916408 Hom.: 1243 Cov.: 5 AF XY: 0.0807 AC XY: 35351 AN XY: 438204

African (AFR) AF: 0.157 AC: 2676 AN: 17004

American (AMR) AF: 0.0528 AC: 351 AN: 6650

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 772 AN: 8136

East Asian (EAS) AF: 0.0151 AC: 88 AN: 5834

South Asian (SAS) AF: 0.0660 AC: 1899 AN: 28788

European-Finnish (FIN) AF: 0.0957 AC: 560 AN: 5850

Middle Eastern (MID) AF: 0.144 AC: 284 AN: 1966

European-Non Finnish (NFE) AF: 0.0796 AC: 64586 AN: 810940

Other (OTH) AF: 0.0811 AC: 2535 AN: 31240

GnomAD4 genome AF: 0.101 AC: 14647 AN: 144370 Hom.: 821 Cov.: 28 AF XY: 0.101 AC XY: 7085 AN XY: 70296

African (AFR) AF: 0.154 AC: 6142 AN: 39994

American (AMR) AF: 0.0695 AC: 1019 AN: 14652

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 376 AN: 3366

East Asian (EAS) AF: 0.0177 AC: 87 AN: 4926

South Asian (SAS) AF: 0.0733 AC: 347 AN: 4734

European-Finnish (FIN) AF: 0.117 AC: 980 AN: 8350

Middle Eastern (MID) AF: 0.145 AC: 41 AN: 282

European-Non Finnish (NFE) AF: 0.0839 AC: 5470 AN: 65168

Other (OTH) AF: 0.0863 AC: 174 AN: 2016

Alfa AF: 0.0208 Hom.: 16

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Exudative vitreoretinopathy 4 (1)
-	1	-	Optic atrophy (1)
-	-	1	Osteoporosis with pseudoglioma (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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

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; COSMIC: COSV53717783;