dbSNP rs1012672: LRP6:p.Cys1270Cys (chr12-12131981-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002336.3(LRP6):c.3810C>T(p.Cys1270Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0661 in 1,613,826 control chromosomes in the GnomAD database, including 3,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.057 ( 309 hom., cov: 31)

Exomes 𝑓: 0.067 ( 3589 hom. )

Consequence

LRP6
NM_002336.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.763

Publications

26 publications found

Variant links:

Genes affected

LRP6 (HGNC:6698): (LDL receptor related protein 6) This gene encodes a member of the low density lipoprotein (LDL) receptor gene family. LDL receptors are transmembrane cell surface proteins involved in receptor-mediated endocytosis of lipoprotein and protein ligands. The protein encoded by this gene functions as a receptor or, with Frizzled, a co-receptor for Wnt and thereby transmits the canonical Wnt/beta-catenin signaling cascade. Through its interaction with the Wnt/beta-catenin signaling cascade this gene plays a role in the regulation of cell differentiation, proliferation, and migration and the development of many cancer types. This protein undergoes gamma-secretase dependent RIP- (regulated intramembrane proteolysis) processing but the precise locations of the cleavage sites have not been determined.[provided by RefSeq, Dec 2009]

LRP6 links:

BCL2L14 (HGNC:16657): (BCL2 like 14) The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. Overexpression of this gene has been shown to induce apoptosis in cells. Three alternatively spliced transcript variants encoding two distinct isoforms have been reported for this gene. [provided by RefSeq, May 2009]

BCL2L14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 12-12131981-G-A is Benign according to our data. Variant chr12-12131981-G-A is described in ClinVar as Benign. ClinVar VariationId is 1237676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.763 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0679 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002336.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRP6	NM_002336.3	MANE Select	c.3810C>T	p.Cys1270Cys	synonymous	Exon 18 of 23	NP_002327.2	O75581
LRP6	NM_001414244.1		c.3903C>T	p.Cys1301Cys	synonymous	Exon 19 of 24	NP_001401173.1
LRP6	NM_001414245.1		c.3810C>T	p.Cys1270Cys	synonymous	Exon 18 of 24	NP_001401174.1	O75581

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRP6	ENST00000261349.9	TSL:1 MANE Select	c.3810C>T	p.Cys1270Cys	synonymous	Exon 18 of 23	ENSP00000261349.4	O75581
LRP6	ENST00000543091.1	TSL:1	c.3734-59C>T		intron	N/A	ENSP00000442472.1	F5H7J9
LRP6	ENST00000538239.5	TSL:1	n.3402C>T		non_coding_transcript_exon	Exon 17 of 24	ENSP00000445083.1	H0YGW5

Frequencies

GnomAD3 genomes

AF:

0.0572

AC:

8696

AN:

151962

Hom.:

310

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0342

Gnomad AMI

AF:

0.0418

Gnomad AMR

AF:

0.0541

Gnomad ASJ

AF:

0.121

Gnomad EAS

AF:

0.0168

Gnomad SAS

AF:

0.0231

Gnomad FIN

AF:

0.0806

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.0696

Gnomad OTH

AF:

0.0768

GnomAD2 exomes

AF:

0.0590

AC:

14826

AN:

251216

AF XY:

0.0597

show subpopulations

Gnomad AFR exome

AF:

0.0334

Gnomad AMR exome

AF:

0.0453

Gnomad ASJ exome

AF:

0.125

Gnomad EAS exome

AF:

0.0124

Gnomad FIN exome

AF:

0.0793

Gnomad NFE exome

AF:

0.0702

Gnomad OTH exome

AF:

0.0808

GnomAD4 exome

AF:

0.0670

AC:

97947

AN:

1461746

Hom.:

3589

Cov.:

AF XY:

0.0663

AC XY:

48245

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.0347

AC:

1162

AN:

33480

American (AMR)

AF:

0.0481

AC:

2151

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

3362

AN:

26136

East Asian (EAS)

AF:

0.0302

AC:

1197

AN:

39698

South Asian (SAS)

AF:

0.0339

AC:

2921

AN:

86256

European-Finnish (FIN)

AF:

0.0792

AC:

4233

AN:

53416

Middle Eastern (MID)

AF:

0.140

AC:

808

AN:

5764

European-Non Finnish (NFE)

AF:

0.0700

AC:

77805

AN:

1111880

Other (OTH)

AF:

0.0713

AC:

4308

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

5048

10096

15145

20193

25241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2902

5804

8706

11608

14510

<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:

0.0572

AC:

8703

AN:

152080

Hom.:

309

Cov.:

AF XY:

0.0576

AC XY:

4285

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0343

AC:

1424

AN:

41502

American (AMR)

AF:

0.0540

AC:

824

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

420

AN:

3470

East Asian (EAS)

AF:

0.0172

AC:

AN:

5176

South Asian (SAS)

AF:

0.0239

AC:

115

AN:

4808

European-Finnish (FIN)

AF:

0.0806

AC:

852

AN:

10574

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0696

AC:

4730

AN:

67982

Other (OTH)

AF:

0.0760

AC:

160

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

425

850

1275

1700

2125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0688

Hom.:

791

Bravo

AF:

0.0566

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.0750

EpiControl

AF:

0.0759

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.32

(source)

DANN

Benign

0.81

PhyloP100

-0.76

PromoterAI

-0.0021

Neutral

(source)

Mutation Taster

=97/3

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