chr12-12159794-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002336.3(LRP6):c.2450C>G(p.Ser817Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,614,106 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00045 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 7 hom. )

Consequence

LRP6
NM_002336.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.76

Publications

13 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011114866).

BP6

Variant 12-12159794-G-C is Benign according to our data. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12159794-G-C is described in CliVar as Benign. Clinvar id is 1617015.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000447 (68/152294) while in subpopulation EAS AF = 0.0118 (61/5190). AF 95% confidence interval is 0.00939. There are 1 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 68 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3 link	c.2450C>G	p.Ser817Cys	missense_variant	Exon 11 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.2450C>G	p.Ser817Cys	missense_variant	Exon 11 of 23	1	NM_002336.3	ENSP00000261349.4	O75581
LRP6	ENST00000543091.1 link	c.2450C>G	p.Ser817Cys	missense_variant	Exon 11 of 23	1		ENSP00000442472.1	F5H7J9
LRP6	ENST00000538239.5 link	n.2042C>G		non_coding_transcript_exon_variant	Exon 10 of 24	1		ENSP00000445083.1	H0YGW5
BCL2L14	ENST00000298566.2 link	n.*24+20815G>C		intron_variant	Intron 5 of 6	2		ENSP00000298566.1	Q9BZR8-3

Frequencies

GnomAD3 genomes

AF:

0.000453

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0119

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000879

AC:

221

AN:

251394

AF XY:

0.000743

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0115

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000260

AC:

380

AN:

1461812

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

176

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00761

AC:

302

AN:

39680

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111972

Other (OTH)

AF:

0.00114

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000447

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0118

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000171

Hom.:

Bravo

AF:

0.000514

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000865

AC:

105

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

D;T

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.9

L;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.8

N;N

REVEL

Pathogenic

0.77

Sift

Benign

0.18

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.84

P;D

Vest4

0.65

MVP

0.78

MPC

0.65

ClinPred

0.071

GERP RS

5.8

Varity_R

0.38

gMVP

0.79

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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