11-68312746-CGCTGCT-C

Variant names:

• chr11-68312746-CGCTGCT-C
• rs72555376
• NM_002335.4:c.55_60delCTGCTG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_002335.4(LRP5):​c.55_60delCTGCTG​(p.Leu19_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 0.000307 in 1,060,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L19L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: LRP5 NM_002335.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 11-68312746-CGCTGCT-C is Benign according to our data. Variant chr11-68312746-CGCTGCT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286883.

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_60delCTGCTG	p.Leu19_Leu20del	conservative_inframe_deletion	Exon 1 of 23	NP_002326.2
	LRP5	NM_001291902.2		c.-1711_-1706delCTGCTG		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_60delCTGCTG	p.Leu19_Leu20del	conservative_inframe_deletion	Exon 1 of 23	ENSP00000294304.6
	LRP5	ENST00000529993.5	TSL:1	n.55_60delCTGCTG		non_coding_transcript_exon	Exon 1 of 23	ENSP00000436652.1
	LRP5	ENST00000909991.1		c.55_60delCTGCTG	p.Leu19_Leu20del	conservative_inframe_deletion	Exon 1 of 23	ENSP00000580050.1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 39 AN: 144332 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000137

Gnomad ASJ AF: 0.000297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00671

Gnomad NFE AF: 0.000307

Gnomad OTH AF: 0.00150

GnomAD2 exomes AF: 0.00 AC: 0 AN: 16308 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000313 AC: 287 AN: 915972 Hom.: 0 AF XY: 0.000327 AC XY: 143 AN XY: 437958

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000118 AC: 2 AN: 17000

American (AMR) AF: 0.00106 AC: 7 AN: 6612

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 7 AN: 8106

East Asian (EAS) AF: 0.000858 AC: 5 AN: 5830

South Asian (SAS) AF: 0.000801 AC: 23 AN: 28710

European-Finnish (FIN) AF: 0.000512 AC: 3 AN: 5854

Middle Eastern (MID) AF: 0.00204 AC: 4 AN: 1960

European-Non Finnish (NFE) AF: 0.000276 AC: 224 AN: 810664

Other (OTH) AF: 0.000384 AC: 12 AN: 31236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000270 AC: 39 AN: 144418 Hom.: 0 Cov.: 28 AF XY: 0.000213 AC XY: 15 AN XY: 70314

African (AFR) AF: 0.000250 AC: 10 AN: 40018

American (AMR) AF: 0.000136 AC: 2 AN: 14654

Ashkenazi Jewish (ASJ) AF: 0.000297 AC: 1 AN: 3366

East Asian (EAS) AF: 0.00 AC: 0 AN: 4926

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8356

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.000307 AC: 20 AN: 65182

Other (OTH) AF: 0.00149 AC: 3 AN: 2016

Alfa AF: 0.00 Hom.: 16

Bravo AF: 0.000378

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=173/27	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;