rs10845493

Variant names:

• chr12-12179262-C-T
• rs10845493
• NM_002336.3:c.1545+548G>A

Variant summary

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

The NM_002336.3(LRP6):​c.1545+548G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 151,986 control chromosomes in the GnomAD database, including 1,047 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 0.10 (1047 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.292
• 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]

BCL2L14 (HGNC:16657): (BCL2 like 14) The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. Overexpression of this gene has been shown to induce apoptosis in cells. Three alternatively spliced transcript variants encoding two distinct isoforms have been reported for this gene. [provided by RefSeq, May 2009]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.1545+548G>A		intron_variant	Intron 7 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.1545+548G>A		intron_variant	Intron 7 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.1545+548G>A		intron_variant	Intron 7 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.1137+548G>A		intron_variant	Intron 6 of 23	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*25-8043C>T		intron_variant	Intron 5 of 6	2		ENSP00000298566.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15508 AN: 151868 Hom.: 1048 Cov.: 32

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.0855

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.103

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

GnomAD4 genome AF: 0.102 AC: 15511 AN: 151986 Hom.: 1047 Cov.: 32 AF XY: 0.100 AC XY: 7459 AN XY: 74294

African (AFR) AF: 0.0311 AC: 1290 AN: 41464

American (AMR) AF: 0.0854 AC: 1301 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0509 AC: 245 AN: 4812

European-Finnish (FIN) AF: 0.155 AC: 1636 AN: 10538

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10191 AN: 67962

Other (OTH) AF: 0.102 AC: 215 AN: 2104

Alfa AF: 0.131 Hom.: 847

Bravo AF: 0.0959

Asia WGS AF: 0.0260 AC: 91 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.64
DANN	Benign	0.39
PhyloP100		-0.29
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: rs10845493; hg19: chr12-12332196;