11-68312746-CGCT-C

Variant names:

• chr11-68312746-CGCT-C
• rs72555376
• NM_002335.4:c.58_60delCTG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_002335.4(LRP5):​c.58_60delCTG​(p.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 0.0071 in 951,934 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L20L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0083 (1 hom.)
• Consequence: LRP5 NM_002335.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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 -12 ACMG points.

• BP6: Variant 11-68312746-CGCT-C is Benign according to our data. Variant chr11-68312746-CGCT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00063 (91/144398) while in subpopulation EAS AF = 0.00305 (15/4924). AF 95% confidence interval is 0.00188. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

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_60delCTG	p.Leu20del	conservative_inframe_deletion	Exon 1 of 23	NP_002326.2
	LRP5	NM_001291902.2		c.-1708_-1706delCTG		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_60delCTG	p.Leu20del	conservative_inframe_deletion	Exon 1 of 23	ENSP00000294304.6
	LRP5	ENST00000529993.5	TSL:1	n.58_60delCTG		non_coding_transcript_exon	Exon 1 of 23	ENSP00000436652.1
	LRP5	ENST00000909991.1		c.58_60delCTG	p.Leu20del	conservative_inframe_deletion	Exon 1 of 23	ENSP00000580050.1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 91 AN: 144312 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000820

Gnomad ASJ AF: 0.00119

Gnomad EAS AF: 0.00324

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000479

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000522

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0588 AC: 959 AN: 16308 AF XY: 0.0602

Gnomad AFR exome AF: 0.0367

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.0604

Gnomad EAS exome AF: 0.0985

Gnomad FIN exome AF: 0.0659

Gnomad NFE exome AF: 0.0600

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.00826 AC: 6669 AN: 807536 Hom.: 1 AF XY: 0.00948 AC XY: 3666 AN XY: 386868

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

African (AFR) AF: 0.00592 AC: 91 AN: 15372

American (AMR) AF: 0.0365 AC: 219 AN: 6000

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 154 AN: 7256

East Asian (EAS) AF: 0.0196 AC: 99 AN: 5042

South Asian (SAS) AF: 0.0254 AC: 653 AN: 25668

European-Finnish (FIN) AF: 0.0433 AC: 231 AN: 5330

Middle Eastern (MID) AF: 0.0108 AC: 19 AN: 1758

European-Non Finnish (NFE) AF: 0.00695 AC: 4957 AN: 713534

Other (OTH) AF: 0.00892 AC: 246 AN: 27576

⚠️ 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: 0.000630 AC: 91 AN: 144398 Hom.: 0 Cov.: 28 AF XY: 0.000654 AC XY: 46 AN XY: 70302

African (AFR) AF: 0.000550 AC: 22 AN: 40014

American (AMR) AF: 0.000819 AC: 12 AN: 14654

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 4 AN: 3366

East Asian (EAS) AF: 0.00305 AC: 15 AN: 4924

South Asian (SAS) AF: 0.00 AC: 0 AN: 4736

European-Finnish (FIN) AF: 0.000479 AC: 4 AN: 8348

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

European-Non Finnish (NFE) AF: 0.000522 AC: 34 AN: 65176

Other (OTH) AF: 0.00 AC: 0 AN: 2016

Alfa AF: 0.00 Hom.: 16

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: COSV53711348;