12-12179908-C-T

Position:

chr12-12179908-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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:

LRP6 (HGNC:):

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 made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PM1

In a region_of_interest Beta-propeller 2 (size 261) in uniprot entity LRP6_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_002336.3

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP6. . Gene score misZ 2.7541 (greater than the threshold 3.09). Trascript score misZ 4.2572 (greater than threshold 3.09). GenCC has associacion of gene with coronary artery disease, autosomal dominant 2, tooth agenesis, selective, 7, tooth agenesis.

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 id 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/exons	MANE	Protein	UniProt
LRP6	NM_002336.3 linkuse as main transcript	c.1447G>A	p.Val483Ile	missense_variant	7/23	ENST00000261349.9	NP_002327.2	O75581

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRP6	ENST00000261349.9 linkuse as main transcript	c.1447G>A	p.Val483Ile	missense_variant	7/23	1	NM_002336.3	ENSP00000261349.4	O75581
LRP6	ENST00000543091.1 linkuse as main transcript	c.1447G>A	p.Val483Ile	missense_variant	7/23	1		ENSP00000442472.1	F5H7J9
LRP6	ENST00000538239.5 linkuse as main transcript	n.1039G>A		non_coding_transcript_exon_variant	6/24	1		ENSP00000445083.1	H0YGW5
BCL2L14	ENST00000298566.2 linkuse as main transcript	n.*25-7397C>T		intron_variant		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

GnomAD3 exomes

AF:

0.0133

AC:

3350

AN:

251354

Hom.:

266

AF XY:

0.00965

AC XY:

1311

AN XY:

135850

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 SAS exome

AF:

0.000163

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

Gnomad4 AFR exome

AF:

0.193

Gnomad4 AMR exome

AF:

0.00850

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000229

Gnomad4 OTH exome

AF:

0.0112

GnomAD4 genome

AF:

0.0525

AC:

7991

AN:

152216

Hom.:

705

Cov.:

AF XY:

0.0502

AC XY:

3737

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.183

Gnomad4 AMR

AF:

0.0177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.0374

Alfa

AF:

0.0110

Hom.:

286

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over