12-12223531-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.450-20131T>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.450-20131T>C		intron_variant	Intron 2 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.450-20131T>C		intron_variant	Intron 2 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.42-20131T>C		intron_variant	Intron 1 of 23	1		ENSP00000445083.1
LRP6	ENST00000535731.1	c.-4-20131T>C		intron_variant	Intron 1 of 2	3		ENSP00000439765.1

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

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.505

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.704

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.572

Gnomad4 NFE AF: 0.480

Gnomad4 OTH AF: 0.415

Alfa AF: 0.445 Hom.: 4991

Bravo AF: 0.374

Asia WGS AF: 0.554 AC: 1923 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.9
DANN	Benign	0.89

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: rs11054731; hg19: chr12-12376465;