chr12-12179937-C-T

Position:

chr12-12179937-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP2PP3BS2

The NM_002336.3(LRP6):c.1418G>A(p.Arg473Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,692 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 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

LRP6
NM_002336.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

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:

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 Uncertain_significance. Variant got 0 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, 0.793

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP6	NM_002336.3 linkuse as main transcript	c.1418G>A	p.Arg473Gln	missense_variant	7/23	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9 linkuse as main transcript	c.1418G>A	p.Arg473Gln	missense_variant	7/23	1	NM_002336.3	ENSP00000261349	P1
LRP6	ENST00000543091.1 linkuse as main transcript	c.1418G>A	p.Arg473Gln	missense_variant	7/23	1		ENSP00000442472
LRP6	ENST00000538239.5 linkuse as main transcript	c.1013G>A	p.Arg338Gln	missense_variant, NMD_transcript_variant	6/24	1		ENSP00000445083
BCL2L14	ENST00000298566.2 linkuse as main transcript	c.*25-7368C>T		intron_variant, NMD_transcript_variant		2		ENSP00000298566		Q9BZR8-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251342

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000526

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

0.34

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.85

Sift

Benign

0.055

T;T

Sift4G

Uncertain

0.020

D;D

Polyphen

0.99

D;D

Vest4

0.65

MutPred

0.62

Loss of glycosylation at K470 (P = 0.0982);Loss of glycosylation at K470 (P = 0.0982);

MVP

0.86

MPC

1.5

ClinPred

0.96

GERP RS

5.8

Varity_R

0.62

gMVP

0.88

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