rs10845498

Variant names:

• chr12-12241640-G-A
• rs10845498
• NM_002336.3:c.449+2622C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-12241640-G-A
• chr12-12241640-G-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.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
• Publications: 11 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002336.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	NM_002336.3	MANE Select	c.449+2622C>T		intron	N/A	NP_002327.2
	LRP6	NM_001414244.1		c.449+2622C>T		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.449+2622C>T		intron	N/A	NP_001401174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	ENST00000261349.9	TSL:1 MANE Select	c.449+2622C>T		intron	N/A	ENSP00000261349.4
	LRP6	ENST00000543091.1	TSL:1	c.449+2622C>T		intron	N/A	ENSP00000442472.1
	LRP6	ENST00000538239.5	TSL:1	n.41+2622C>T		intron	N/A	ENSP00000445083.1

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

African (AFR) AF: 0.765 AC: 31615 AN: 41346

American (AMR) AF: 0.814 AC: 12429 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 2656 AN: 3462

East Asian (EAS) AF: 0.831 AC: 4285 AN: 5156

South Asian (SAS) AF: 0.797 AC: 3822 AN: 4798

European-Finnish (FIN) AF: 0.876 AC: 9244 AN: 10556

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55164 AN: 67956

Other (OTH) AF: 0.813 AC: 1716 AN: 2110

Alfa AF: 0.802 Hom.: 5952

Bravo AF: 0.796

Asia WGS AF: 0.809 AC: 2814 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.24
DANN	Benign	0.37
PhyloP100		-1.1
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: rs10845498; hg19: chr12-12394574;