rs2277268

Positions:

• chr11-68406654-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002335.4(LRP5):​c.1932G>A​(p.Glu644Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0671 in 1,614,058 control chromosomes in the GnomAD database, including 3,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (358 hom., cov: 33)
  • Exomes 𝑓: 0.068 (3518 hom.)
• Consequence: LRP5 NM_002335.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.629

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-68406654-G-A is Benign according to our data. Variant chr11-68406654-G-A is described in ClinVar as [Benign]. Clinvar id is 258635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68406654-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-68406654-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.629 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4	c.1932G>A	p.Glu644Glu	synonymous_variant	9/23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.1932G>A	p.Glu644Glu	synonymous_variant	9/23	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*538G>A		non_coding_transcript_exon_variant	9/23	1		ENSP00000436652.1
LRP5	ENST00000529993.5	n.*538G>A		3_prime_UTR_variant	9/23	1		ENSP00000436652.1

Frequencies

GnomAD3 genomes AF: 0.0630 AC: 9590 AN: 152118 Hom.: 357 Cov.: 33

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0581

Gnomad ASJ AF: 0.0495

Gnomad EAS AF: 0.0439

Gnomad SAS AF: 0.0408

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0701

Gnomad OTH AF: 0.0676

GnomAD3 exomes AF: 0.0583 AC: 14656 AN: 251324 Hom.: 465 AF XY: 0.0585 AC XY: 7954 AN XY: 135888

Gnomad AFR exome AF: 0.0669

Gnomad AMR exome AF: 0.0446

Gnomad ASJ exome AF: 0.0488

Gnomad EAS exome AF: 0.0413

Gnomad SAS exome AF: 0.0381

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0724

Gnomad OTH exome AF: 0.0675

GnomAD4 exome AF: 0.0675 AC: 98731 AN: 1461822 Hom.: 3518 Cov.: 33 AF XY: 0.0667 AC XY: 48481 AN XY: 727206

Gnomad4 AFR exome AF: 0.0664

Gnomad4 AMR exome AF: 0.0464

Gnomad4 ASJ exome AF: 0.0474

Gnomad4 EAS exome AF: 0.0413

Gnomad4 SAS exome AF: 0.0377

Gnomad4 FIN exome AF: 0.0445

Gnomad4 NFE exome AF: 0.0728

Gnomad4 OTH exome AF: 0.0702

GnomAD4 genome AF: 0.0631 AC: 9600 AN: 152236 Hom.: 358 Cov.: 33 AF XY: 0.0615 AC XY: 4579 AN XY: 74436

Gnomad4 AFR AF: 0.0638

Gnomad4 AMR AF: 0.0580

Gnomad4 ASJ AF: 0.0495

Gnomad4 EAS AF: 0.0436

Gnomad4 SAS AF: 0.0411

Gnomad4 FIN AF: 0.0449

Gnomad4 NFE AF: 0.0702

Gnomad4 OTH AF: 0.0678

Alfa AF: 0.0723 Hom.: 542

Bravo AF: 0.0662

Asia WGS AF: 0.0740 AC: 257 AN: 3478

EpiCase AF: 0.0763

EpiControl AF: 0.0808

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.9
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2277268; hg19: chr11-68174122; COSMIC: COSV53714774; COSMIC: COSV53714774;