12-12223531-A-G

Variant names:

• chr12-12223531-A-G
• rs11054731
• NM_002336.3:c.450-20131T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002336.3(LRP6):​c.450-20131T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 152,084 control chromosomes in the GnomAD database, including 14,485 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (14485 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.144
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• tooth agenesis

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• tooth agenesis, selective, 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• coronary artery disease, autosomal dominant 2

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002336.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	NM_002336.3	MANE Select	c.450-20131T>C		intron	N/A	NP_002327.2
	LRP6	NM_001414244.1		c.450-20131T>C		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.450-20131T>C		intron	N/A	NP_001401174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	ENST00000261349.9	TSL:1 MANE Select	c.450-20131T>C		intron	N/A	ENSP00000261349.4
	LRP6	ENST00000543091.1	TSL:1	c.450-20131T>C		intron	N/A	ENSP00000442472.1
	LRP6	ENST00000538239.5	TSL:1	n.42-20131T>C		intron	N/A	ENSP00000445083.1

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59818 AN: 151966 Hom.: 14501 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.704

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.416

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.393 AC: 59803 AN: 152084 Hom.: 14485 Cov.: 32 AF XY: 0.406 AC XY: 30181 AN XY: 74346

African (AFR) AF: 0.103 AC: 4278 AN: 41508

American (AMR) AF: 0.505 AC: 7715 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1469 AN: 3466

East Asian (EAS) AF: 0.704 AC: 3645 AN: 5178

South Asian (SAS) AF: 0.552 AC: 2659 AN: 4820

European-Finnish (FIN) AF: 0.572 AC: 6038 AN: 10556

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.480 AC: 32645 AN: 67954

Other (OTH) AF: 0.415 AC: 879 AN: 2116

Alfa AF: 0.443 Hom.: 8983

Bravo AF: 0.374

Asia WGS AF: 0.554 AC: 1923 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.9
DANN	Benign	0.89
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11054731; hg19: chr12-12376465;