rs7308022

Positions:

• chr12-12252938-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.56-8283T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 152,148 control chromosomes in the GnomAD database, including 2,055 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 0.14 (2055 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.439

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP6	NM_002336.3	c.56-8283T>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.56-8283T>C		intron_variant		1	NM_002336.3	ENSP00000261349	P1
LRP6	ENST00000543091.1	c.56-8283T>C		intron_variant		1		ENSP00000442472
LRP6	ENST00000535731.1	c.-5+13743T>C		intron_variant		3		ENSP00000439765

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21284 AN: 152030 Hom.: 2048 Cov.: 32

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0911

Gnomad EAS AF: 0.00481

Gnomad SAS AF: 0.0369

Gnomad FIN AF: 0.0676

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0928

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.140 AC: 21322 AN: 152148 Hom.: 2055 Cov.: 32 AF XY: 0.137 AC XY: 10152 AN XY: 74362

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.0911

Gnomad4 EAS AF: 0.00482

Gnomad4 SAS AF: 0.0373

Gnomad4 FIN AF: 0.0676

Gnomad4 NFE AF: 0.0928

Gnomad4 OTH AF: 0.136

Alfa AF: 0.124 Hom.: 250

Bravo AF: 0.152

Asia WGS AF: 0.0380 AC: 130 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.9
DANN	Benign	0.28

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: rs7308022; hg19: chr12-12405872;