NM_002335.4:c.2220C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002335.4(LRP5):c.2220C>T(p.Asn740Asn) 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:11O:1

Conservation

PhyloP100: 0.276

Publications

64 publications found

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 Gene-Disease associations (from GenCC):

bone mineral density quantitative trait locus 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
LRP5-related exudative vitreoretinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
osteoporosis-pseudoglioma syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
exudative vitreoretinopathy 4
Inheritance: Unknown, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal dominant osteosclerosis, Worth type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
polycystic liver disease 4 with or without kidney cysts
Inheritance: AD Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
autosomal dominant osteopetrosis 1
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
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

LRP5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 193639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002335.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP5	NM_002335.4	MANE Select	c.2220C>T	p.Asn740Asn	synonymous	Exon 10 of 23	NP_002326.2	O75197
	LRP5	NM_001291902.2		c.477C>T	p.Asn159Asn	synonymous	Exon 10 of 23	NP_001278831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRP5	ENST00000294304.12	TSL:1 MANE Select	c.2220C>T	p.Asn740Asn	synonymous	Exon 10 of 23	ENSP00000294304.6	O75197
LRP5	ENST00000529993.5	TSL:1	n.*826C>T		non_coding_transcript_exon	Exon 10 of 23	ENSP00000436652.1	E9PHY1
LRP5	ENST00000529993.5	TSL:1	n.*826C>T		3_prime_UTR	Exon 10 of 23	ENSP00000436652.1	E9PHY1

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

GnomAD2 exomes

AF:

0.136

AC:

34275

AN:

251274

AF XY:

0.133

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 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

African (AFR)

AF:

0.0389

AC:

1304

AN:

33480

American (AMR)

AF:

0.188

AC:

8413

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.154

AC:

4015

AN:

26134

East Asian (EAS)

AF:

0.231

AC:

9162

AN:

39700

South Asian (SAS)

AF:

0.0815

AC:

7032

AN:

86258

European-Finnish (FIN)

AF:

0.0503

AC:

2684

AN:

53372

Middle Eastern (MID)

AF:

0.135

AC:

776

AN:

5768

European-Non Finnish (NFE)

AF:

0.163

AC:

180784

AN:

1111862

Other (OTH)

AF:

0.142

AC:

8581

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

10942

21884

32826

43768

54710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6498

12996

19494

25992

32490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.118

AC:

18015

AN:

152140

Hom.:

1352

Cov.:

AF XY:

0.114

AC XY:

8461

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0467

AC:

1941

AN:

41536

American (AMR)

AF:

0.160

AC:

2445

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

493

AN:

3468

East Asian (EAS)

AF:

0.199

AC:

1029

AN:

5158

South Asian (SAS)

AF:

0.0843

AC:

406

AN:

4814

European-Finnish (FIN)

AF:

0.0429

AC:

455

AN:

10600

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.154

AC:

10479

AN:

67980

Other (OTH)

AF:

0.143

AC:

302

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

773

1546

2319

3092

3865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

198

396

594

792

990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.148

Hom.:

6891

Bravo

AF:

0.132

Asia WGS

AF:

0.125

AC:

436

AN:

3478

EpiCase

AF:

0.161

EpiControl

AF:

0.158

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Disorder of bone (1)

Osteogenesis imperfecta (1)

Bone mineral density quantitative trait locus 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.6

(source)

DANN

Benign

0.84

PhyloP100

0.28

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over