rs2277268

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.629
Variant links:
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]

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ACMG classification

Classification made for transcript

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
LRP5NM_002335.4 linkuse as main transcriptc.1932G>A p.Glu644Glu synonymous_variant 9/23 ENST00000294304.12 NP_002326.2 O75197

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRP5ENST00000294304.12 linkuse as main transcriptc.1932G>A p.Glu644Glu synonymous_variant 9/231 NM_002335.4 ENSP00000294304.6 O75197
LRP5ENST00000529993.5 linkuse as main transcriptn.*538G>A non_coding_transcript_exon_variant 9/231 ENSP00000436652.1 E9PHY1
LRP5ENST00000529993.5 linkuse as main transcriptn.*538G>A 3_prime_UTR_variant 9/231 ENSP00000436652.1 E9PHY1

Frequencies

GnomAD3 genomes
AF:
0.0630
AC:
9590
AN:
152118
Hom.:
357
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2277268; hg19: chr11-68174122; COSMIC: COSV53714774; COSMIC: COSV53714774; API