rs2242340

Positions:

• chr11-68446651-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002335.4(LRP5):​c.4586+118C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0916 in 907,300 control chromosomes in the GnomAD database, including 4,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (613 hom., cov: 32)
  • Exomes 𝑓: 0.093 (3612 hom.)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.94

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-68446651-C-T is Benign according to our data. Variant chr11-68446651-C-T is described in ClinVar as [Benign]. Clinvar id is 1175466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP5	NM_002335.4	c.4586+118C>T		intron_variant		ENST00000294304.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP5	ENST00000294304.12	c.4586+118C>T		intron_variant		1	NM_002335.4	P1
LRP5	ENST00000529993.5	c.*3192+118C>T		intron_variant, NMD_transcript_variant		1
LRP5	ENST00000529702.1	c.256+118C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0837 AC: 12724 AN: 152078 Hom.: 613 Cov.: 32

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.0814

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0199

Gnomad SAS AF: 0.0462

Gnomad FIN AF: 0.0871

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.108

GnomAD4 exome AF: 0.0932 AC: 70382 AN: 755104 Hom.: 3612 AF XY: 0.0915 AC XY: 36291 AN XY: 396720

Gnomad4 AFR exome AF: 0.0505

Gnomad4 AMR exome AF: 0.0693

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.0285

Gnomad4 SAS exome AF: 0.0449

Gnomad4 FIN exome AF: 0.0879

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 0.0992

GnomAD4 genome AF: 0.0836 AC: 12725 AN: 152196 Hom.: 613 Cov.: 32 AF XY: 0.0814 AC XY: 6057 AN XY: 74388

Gnomad4 AFR AF: 0.0493

Gnomad4 AMR AF: 0.0813

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.0200

Gnomad4 SAS AF: 0.0460

Gnomad4 FIN AF: 0.0871

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0935 Hom.: 99

Bravo AF: 0.0840

Asia WGS AF: 0.0500 AC: 175 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.90
CADD	Benign	1.7
DANN	Benign	0.66

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: rs2242340; hg19: chr11-68214119;