chr12-12259861-T-C

Variant names:

• chr12-12259861-T-C
• rs10743980
• NM_002336.3:c.55+6820A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002336.3(LRP6):​c.55+6820A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 151,980 control chromosomes in the GnomAD database, including 22,778 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 0.54 (22778 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.266
• Publications: 16 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.55+6820A>G		intron_variant	Intron 1 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.55+6820A>G		intron_variant	Intron 1 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.55+6820A>G		intron_variant	Intron 1 of 22	1		ENSP00000442472.1
LRP6	ENST00000535731.1	c.-5+6820A>G		intron_variant	Intron 1 of 2	3		ENSP00000439765.1

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81404 AN: 151862 Hom.: 22782 Cov.: 32

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.551

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

GnomAD4 genome AF: 0.536 AC: 81433 AN: 151980 Hom.: 22778 Cov.: 32 AF XY: 0.547 AC XY: 40656 AN XY: 74262

African (AFR) AF: 0.368 AC: 15228 AN: 41420

American (AMR) AF: 0.637 AC: 9716 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1858 AN: 3470

East Asian (EAS) AF: 0.764 AC: 3954 AN: 5174

South Asian (SAS) AF: 0.675 AC: 3251 AN: 4816

European-Finnish (FIN) AF: 0.640 AC: 6750 AN: 10550

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.572 AC: 38909 AN: 67970

Other (OTH) AF: 0.553 AC: 1167 AN: 2112

Alfa AF: 0.558 Hom.: 38454

Bravo AF: 0.526

Asia WGS AF: 0.682 AC: 2369 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	13
DANN	Benign	0.66
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs10743980; hg19: chr12-12412795;