rs141212743

Positions:

chr12-12181337-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PP2PP3BS1_SupportingBS2

The NM_002336.3(LRP6):c.1079G>A(p.Arg360His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

LRP6
NM_002336.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 7.91

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 Likely_benign. Variant got -1 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000125 (19/152224) while in subpopulation NFE AF= 0.000221 (15/68006). AF 95% confidence interval is 0.000135. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP6	NM_002336.3 linkuse as main transcript	c.1079G>A	p.Arg360His	missense_variant	6/23	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.1079G>A	p.Arg360His	missense_variant	6/23	1	NM_002336.3	ENSP00000261349.4	O75581
LRP6	ENST00000543091.1 linkuse as main transcript	c.1079G>A	p.Arg360His	missense_variant	6/23	1		ENSP00000442472.1	F5H7J9
LRP6	ENST00000538239.5 linkuse as main transcript	n.671G>A		non_coding_transcript_exon_variant	5/24	1		ENSP00000445083.1	H0YGW5
BCL2L14	ENST00000298566.2 linkuse as main transcript	n.*25-5968C>T		intron_variant		2		ENSP00000298566.1	Q9BZR8-3

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251304

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000255

AC:

372

AN:

1461582

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

184

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000301

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000125

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000289

Hom.:

Bravo

AF:

0.000140

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with coronary artery disease in published literature (Singh et al., 2013); This variant is associated with the following publications: (PMID: 23703864, 31589614) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 22, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRP6 protein function. ClinVar contains an entry for this variant (Variation ID: 66056). This missense change has been observed in individual(s) with coronary artery disease (PMID: 23703864). This variant is present in population databases (rs141212743, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 360 of the LRP6 protein (p.Arg360His). -

Coronary artery disease, autosomal dominant 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

1.6

L;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

1.0

D;D

Vest4

0.83

MVP

0.89

MPC

1.5

ClinPred

0.46

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.67

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