NM_002335.4:c.2318+120C>T

Variant names:

• chr11-68410260-C-T
• rs667126
• NM_002335.4:c.2318+120C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002335.4(LRP5):​c.2318+120C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 812,530 control chromosomes in the GnomAD database, including 231,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.69 (37547 hom., cov: 32)
  • Exomes 𝑓: 0.76 (193512 hom.)
• Consequence: LRP5 NM_002335.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• bone mineral density quantitative trait locus 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• exudative vitreoretinopathy 4

  Inheritance: AD, SD, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• osteoporosis-pseudoglioma syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant osteosclerosis, Worth type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• polycystic liver disease 4 with or without kidney cysts

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal dominant osteopetrosis 1

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• exudative vitreoretinopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyperostosis corticalis generalisata

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteosclerosis-developmental delay-craniosynostosis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• polycystic liver disease 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-68410260-C-T is Benign according to our data. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-68410260-C-T is described in CliVar as Benign. Clinvar id is 1291233.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP5	NM_002335.4	c.2318+120C>T		intron_variant	Intron 10 of 22	ENST00000294304.12	NP_002326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP5	ENST00000294304.12	c.2318+120C>T		intron_variant	Intron 10 of 22	1	NM_002335.4	ENSP00000294304.6
LRP5	ENST00000529993.5	n.*924+120C>T		intron_variant	Intron 10 of 22	1		ENSP00000436652.1
LRP5	ENST00000528714.1	n.112+120C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104415 AN: 151962 Hom.: 37541 Cov.: 32

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.716

Gnomad ASJ AF: 0.751

Gnomad EAS AF: 0.782

Gnomad SAS AF: 0.841

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.757

Gnomad OTH AF: 0.679

GnomAD4 exome AF: 0.762 AC: 503391 AN: 660450 Hom.: 193512 AF XY: 0.768 AC XY: 269194 AN XY: 350588

African (AFR) AF: 0.470 AC: 8322 AN: 17722

American (AMR) AF: 0.736 AC: 25601 AN: 34800

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 15155 AN: 20560

East Asian (EAS) AF: 0.735 AC: 23840 AN: 32420

South Asian (SAS) AF: 0.836 AC: 53532 AN: 64062

European-Finnish (FIN) AF: 0.913 AC: 37416 AN: 41002

Middle Eastern (MID) AF: 0.739 AC: 2008 AN: 2718

European-Non Finnish (NFE) AF: 0.756 AC: 312350 AN: 413244

Other (OTH) AF: 0.742 AC: 25167 AN: 33922

GnomAD4 genome AF: 0.687 AC: 104449 AN: 152080 Hom.: 37547 Cov.: 32 AF XY: 0.699 AC XY: 51968 AN XY: 74340

African (AFR) AF: 0.469 AC: 19435 AN: 41412

American (AMR) AF: 0.716 AC: 10943 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 2609 AN: 3472

East Asian (EAS) AF: 0.782 AC: 4043 AN: 5172

South Asian (SAS) AF: 0.841 AC: 4049 AN: 4816

European-Finnish (FIN) AF: 0.927 AC: 9833 AN: 10610

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.757 AC: 51480 AN: 67998

Other (OTH) AF: 0.681 AC: 1438 AN: 2112

Alfa AF: 0.743 Hom.: 11940

Bravo AF: 0.655

Asia WGS AF: 0.788 AC: 2738 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.12
DANN	Benign	0.53
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs667126; hg19: chr11-68177728;