rs2306862

Positions:

chr11-68410042-C-T

Variant summary

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

The NM_002335.4(LRP5):c.2220C>T(p.Asn740=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,613,820 control chromosomes in the GnomAD database, including 19,522 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1352 hom., cov: 31)

Exomes 𝑓: 0.15 ( 18170 hom. )

Consequence

LRP5
NM_002335.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.276

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]

LRP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 11-68410042-C-T is Benign according to our data. Variant chr11-68410042-C-T is described in ClinVar as [Benign]. Clinvar id is 193639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68410042-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-68410042-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.276 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP5	NM_002335.4 linkuse as main transcript	c.2220C>T	p.Asn740=	synonymous_variant	10/23	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LRP5	ENST00000294304.12 linkuse as main transcript	c.2220C>T	p.Asn740=	synonymous_variant	10/23	1	NM_002335.4	ENSP00000294304	P1
LRP5	ENST00000529993.5 linkuse as main transcript	c.*826C>T		3_prime_UTR_variant, NMD_transcript_variant	10/23	1		ENSP00000436652
LRP5	ENST00000528714.1 linkuse as main transcript	n.14C>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

18011

AN:

152022

Hom.:

1352

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0468

Gnomad AMI

AF:

0.462

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.200

Gnomad SAS

AF:

0.0841

Gnomad FIN

AF:

0.0429

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.142

GnomAD3 exomes

AF:

0.136

AC:

34275

AN:

251274

Hom.:

2709

AF XY:

0.133

AC XY:

18022

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0464

Gnomad AMR exome

AF:

0.193

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.199

Gnomad SAS exome

AF:

0.0809

Gnomad FIN exome

AF:

0.0472

Gnomad NFE exome

AF:

0.152

Gnomad OTH exome

AF:

0.143

GnomAD4 exome

AF:

0.152

AC:

222751

AN:

1461680

Hom.:

18170

Cov.:

AF XY:

0.150

AC XY:

109128

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0389

Gnomad4 AMR exome

AF:

0.188

Gnomad4 ASJ exome

AF:

0.154

Gnomad4 EAS exome

AF:

0.231

Gnomad4 SAS exome

AF:

0.0815

Gnomad4 FIN exome

AF:

0.0503

Gnomad4 NFE exome

AF:

0.163

Gnomad4 OTH exome

AF:

0.142

GnomAD4 genome

AF:

0.118

AC:

18015

AN:

152140

Hom.:

1352

Cov.:

AF XY:

0.114

AC XY:

8461

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0467

Gnomad4 AMR

AF:

0.160

Gnomad4 ASJ

AF:

0.142

Gnomad4 EAS

AF:

0.199

Gnomad4 SAS

AF:

0.0843

Gnomad4 FIN

AF:

0.0429

Gnomad4 NFE

AF:

0.154

Gnomad4 OTH

AF:

0.143

Alfa

AF:

0.152

Hom.:

3199

Bravo

AF:

0.132

Asia WGS

AF:

0.125

AC:

436

AN:

3478

EpiCase

AF:

0.161

EpiControl

AF:

0.158

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22511589, 17505772, 16115379) -

Osteogenesis imperfecta

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 18, 2022

- -

Increased bone mineral density

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 19, 2022

- -

Bone mineral density quantitative trait locus 1

Other:1

Affects, no assertion criteria provided

literature only

OMIM

Jan 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.6

DANN

Benign

0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over