11-68312746-CGCT-C

Position:

• chr11-68312746-CGCT-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_002335.4(LRP5):​c.58_60del​(p.Leu20del) variant causes a 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0083 (1 hom.)
• Consequence: LRP5 NM_002335.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-68312746-CGCT-C is Benign according to our data. Variant chr11-68312746-CGCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 193232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68312746-CGCT-C is described in Lovd as [Likely_benign]. Variant chr11-68312746-CGCT-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00826 (6669/807536) while in subpopulation AMR AF= 0.0365 (219/6000). AF 95% confidence interval is 0.0325. There are 1 homozygotes in gnomad4_exome. There are 3666 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.58_60del	p.Leu20del	inframe_deletion	1/23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.58_60del	p.Leu20del	inframe_deletion	1/23	1	NM_002335.4	ENSP00000294304	P1
LRP5	ENST00000529993.5	c.58_60del	p.Leu20del	inframe_deletion, NMD_transcript_variant	1/23	1		ENSP00000436652

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

GnomAD3 exomes AF: 0.0588 AC: 959 AN: 16308 Hom.: 0 AF XY: 0.0602 AC XY: 593 AN XY: 9856

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 SAS exome AF: 0.0629

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

Gnomad4 AFR exome AF: 0.00592

Gnomad4 AMR exome AF: 0.0365

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.0196

Gnomad4 SAS exome AF: 0.0254

Gnomad4 FIN exome AF: 0.0433

Gnomad4 NFE exome AF: 0.00695

Gnomad4 OTH exome AF: 0.00892

GnomAD4 genome AF: 0.000630 AC: 91 AN: 144398 Hom.: 0 Cov.: 28 AF XY: 0.000654 AC XY: 46 AN XY: 70302

Gnomad4 AFR AF: 0.000550

Gnomad4 AMR AF: 0.000819

Gnomad4 ASJ AF: 0.00119

Gnomad4 EAS AF: 0.00305

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000479

Gnomad4 NFE AF: 0.000522

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs72555376; hg19: chr11-68080214;