chr12-12241640-G-A

Position:

• chr12-12241640-G-A

Variant summary

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

The NM_002336.3(LRP6):​c.449+2622C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 151,860 control chromosomes in the GnomAD database, including 48,993 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 0.80 (48993 hom., cov: 29)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07

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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP6	NM_002336.3	c.449+2622C>T		intron_variant		ENST00000261349.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP6	ENST00000261349.9	c.449+2622C>T		intron_variant		1	NM_002336.3	P1
LRP6	ENST00000543091.1	c.449+2622C>T		intron_variant		1
LRP6	ENST00000538239.5	c.43+2622C>T		intron_variant, NMD_transcript_variant		1
LRP6	ENST00000535731.1	c.-5+25041C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.803 AC: 121802 AN: 151742 Hom.: 48958 Cov.: 29

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.876

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.814

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

GnomAD4 genome AF: 0.803 AC: 121895 AN: 151860 Hom.: 48993 Cov.: 29 AF XY: 0.808 AC XY: 60009 AN XY: 74224

Gnomad4 AFR AF: 0.765

Gnomad4 AMR AF: 0.814

Gnomad4 ASJ AF: 0.767

Gnomad4 EAS AF: 0.831

Gnomad4 SAS AF: 0.797

Gnomad4 FIN AF: 0.876

Gnomad4 NFE AF: 0.812

Gnomad4 OTH AF: 0.813

Alfa AF: 0.804 Hom.: 5725

Bravo AF: 0.796

Asia WGS AF: 0.809 AC: 2814 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.24
DANN	Benign	0.37

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: rs10845498; hg19: chr12-12394574;