NM_002335.4:c.2318+6T>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002335.4(LRP5):c.2318+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 1,611,592 control chromosomes in the GnomAD database, including 3,926 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 371 hom., cov: 31)

Exomes 𝑓: 0.068 ( 3555 hom. )

Consequence

LRP5
NM_002335.4 splice_region, intron

Scores

Splicing: ADA: 0.001634

Clinical Significance

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

Conservation

PhyloP100: -1.41

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-68410146-T-C is Benign according to our data. Variant chr11-68410146-T-C is described in ClinVar as [Benign]. Clinvar id is 258636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68410146-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4 link	c.2318+6T>C		splice_region_variant, intron_variant	Intron 10 of 22	ENST00000294304.12	NP_002326.2	O75197

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP5	ENST00000294304.12 link	c.2318+6T>C	splice_region_variant, intron_variant	Intron 10 of 22	1	NM_002335.4	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5 link	n.*924+6T>C	splice_region_variant, intron_variant	Intron 10 of 22	1		ENSP00000436652.1	E9PHY1
LRP5	ENST00000528714.1 link	n.112+6T>C	splice_region_variant, intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0635

AC:

9659

AN:

152112

Hom.:

370

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0642

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0584

Gnomad ASJ

AF:

0.0496

Gnomad EAS

AF:

0.0439

Gnomad SAS

AF:

0.0406

Gnomad FIN

AF:

0.0452

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.0707

Gnomad OTH

AF:

0.0703

GnomAD3 exomes

AF:

0.0585

AC:

14432

AN:

246616

Hom.:

448

AF XY:

0.0588

AC XY:

7864

AN XY:

133840

show subpopulations

Gnomad AFR exome

AF:

0.0671

Gnomad AMR exome

AF:

0.0448

Gnomad ASJ exome

AF:

0.0490

Gnomad EAS exome

AF:

0.0409

Gnomad SAS exome

AF:

0.0379

Gnomad FIN exome

AF:

0.0452

Gnomad NFE exome

AF:

0.0731

Gnomad OTH exome

AF:

0.0677

GnomAD4 exome

AF:

0.0681

AC:

99338

AN:

1459362

Hom.:

3555

Cov.:

AF XY:

0.0672

AC XY:

48768

AN XY:

726062

show subpopulations

Gnomad4 AFR exome

AF:

0.0666

Gnomad4 AMR exome

AF:

0.0466

Gnomad4 ASJ exome

AF:

0.0475

Gnomad4 EAS exome

AF:

0.0411

Gnomad4 SAS exome

AF:

0.0376

Gnomad4 FIN exome

AF:

0.0446

Gnomad4 NFE exome

AF:

0.0735

Gnomad4 OTH exome

AF:

0.0706

GnomAD4 genome

AF:

0.0635

AC:

9669

AN:

152230

Hom.:

371

Cov.:

AF XY:

0.0618

AC XY:

4602

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0643

Gnomad4 AMR

AF:

0.0583

Gnomad4 ASJ

AF:

0.0496

Gnomad4 EAS

AF:

0.0436

Gnomad4 SAS

AF:

0.0408

Gnomad4 FIN

AF:

0.0452

Gnomad4 NFE

AF:

0.0707

Gnomad4 OTH

AF:

0.0705

Alfa

AF:

0.0642

Hom.:

166

Bravo

AF:

0.0665

Asia WGS

AF:

0.0720

AC:

251

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.6

DANN

Benign

0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.038

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