chr12-12179908-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002336.3(LRP6):c.1447G>A(p.Val483Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00981 in 1,613,926 control chromosomes in the GnomAD database, including 1,384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 705 hom., cov: 31)

Exomes 𝑓: 0.0054 ( 679 hom. )

Consequence

LRP6
NM_002336.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.06

Publications

14 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018368661).

BP6

Variant 12-12179908-C-T is Benign according to our data. Variant chr12-12179908-C-T is described in ClinVar as Benign. ClinVar VariationId is 1221930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3 link	c.1447G>A	p.Val483Ile	missense_variant	Exon 7 of 23	ENST00000261349.9	NP_002327.2	O75581

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP6	ENST00000261349.9 link	c.1447G>A	p.Val483Ile	missense_variant	Exon 7 of 23	1	NM_002336.3	ENSP00000261349.4	O75581
LRP6	ENST00000543091.1 link	c.1447G>A	p.Val483Ile	missense_variant	Exon 7 of 23	1		ENSP00000442472.1	F5H7J9
LRP6	ENST00000538239.5 link	n.1039G>A		non_coding_transcript_exon_variant	Exon 6 of 24	1		ENSP00000445083.1	H0YGW5
BCL2L14	ENST00000298566.2 link	n.*25-7397C>T		intron_variant	Intron 5 of 6	2		ENSP00000298566.1	Q9BZR8-3

Frequencies

GnomAD3 genomes

AF:

0.0524

AC:

7968

AN:

152098

Hom.:

706

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0378

GnomAD2 exomes

AF:

0.0133

AC:

3350

AN:

251354

AF XY:

0.00965

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.00792

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00536

AC:

7835

AN:

1461710

Hom.:

679

Cov.:

AF XY:

0.00463

AC XY:

3370

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.193

AC:

6466

AN:

33468

American (AMR)

AF:

0.00850

AC:

380

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.000359

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000229

AC:

255

AN:

1111886

Other (OTH)

AF:

0.0112

AC:

679

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

349

699

1048

1398

1747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<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:

0.0525

AC:

7991

AN:

152216

Hom.:

705

Cov.:

AF XY:

0.0502

AC XY:

3737

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.183

AC:

7604

AN:

41494

American (AMR)

AF:

0.0177

AC:

270

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68012

Other (OTH)

AF:

0.0374

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

321

643

964

1286

1607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0217

Hom.:

917

Bravo

AF:

0.0598

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.177

AC:

782

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0162

AC:

1967

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2021

GeneDx

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

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;T

Eigen

Benign

0.042

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.96

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.77

N;.

PhyloP100

5.1

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.46

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.20

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.013

B;B

Vest4

0.21

MPC

0.47

ClinPred

0.015

GERP RS

5.8

Varity_R

0.14

gMVP

0.26

Mutation Taster

=84/16

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over