chr12-12214654-T-G

Variant names:

• chr12-12214654-T-G
• rs1181334
• NM_002336.3:c.450-11254A>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.450-11254A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.851 in 152,184 control chromosomes in the GnomAD database, including 55,333 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 0.85 (55333 hom., cov: 33)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.614
• Publications: 12 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.450-11254A>C		intron_variant	Intron 2 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.450-11254A>C		intron_variant	Intron 2 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.450-11254A>C		intron_variant	Intron 2 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.42-11254A>C		intron_variant	Intron 1 of 23	1		ENSP00000445083.1
LRP6	ENST00000535731.1	c.-4-11254A>C		intron_variant	Intron 1 of 2	3		ENSP00000439765.1

Frequencies

GnomAD3 genomes AF: 0.851 AC: 129425 AN: 152066 Hom.: 55285 Cov.: 33

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.886

Gnomad ASJ AF: 0.842

Gnomad EAS AF: 0.950

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.858

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

GnomAD4 genome AF: 0.851 AC: 129532 AN: 152184 Hom.: 55333 Cov.: 33 AF XY: 0.854 AC XY: 63529 AN XY: 74400

African (AFR) AF: 0.901 AC: 37439 AN: 41540

American (AMR) AF: 0.886 AC: 13544 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.842 AC: 2923 AN: 3472

East Asian (EAS) AF: 0.950 AC: 4921 AN: 5182

South Asian (SAS) AF: 0.891 AC: 4300 AN: 4824

European-Finnish (FIN) AF: 0.810 AC: 8581 AN: 10588

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.810 AC: 55089 AN: 67980

Other (OTH) AF: 0.859 AC: 1815 AN: 2112

Alfa AF: 0.827 Hom.: 34955

Bravo AF: 0.859

Asia WGS AF: 0.910 AC: 3164 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.75
PhyloP100		-0.61
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: rs1181334; hg19: chr12-12367588;