chr12-12212391-A-G

Position:

• chr12-12212391-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002336.3(LRP6):​c.450-8991T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,258 control chromosomes in the GnomAD database, including 1,425 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 0.12 (1425 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP6	NM_002336.3	c.450-8991T>C		intron_variant		ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.450-8991T>C		intron_variant		1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.450-8991T>C		intron_variant		1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.42-8991T>C		intron_variant		1		ENSP00000445083.1
LRP6	ENST00000535731.1	c.-4-8991T>C		intron_variant		3		ENSP00000439765.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18476 AN: 152140 Hom.: 1426 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0586

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.139

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

GnomAD4 genome AF: 0.121 AC: 18471 AN: 152258 Hom.: 1425 Cov.: 32 AF XY: 0.123 AC XY: 9126 AN XY: 74446

Gnomad4 AFR AF: 0.0334

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.0584

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.140

Alfa AF: 0.146 Hom.: 2188

Bravo AF: 0.122

Asia WGS AF: 0.113 AC: 392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.4
DANN	Benign	0.75

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

Other links and lift over

dbSNP: rs17302049; hg19: chr12-12365325;