12-12178441-C-T

Variant names:

• chr12-12178441-C-T
• rs2417085
• NM_002336.3:c.1545+1369G>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+1369G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 151,972 control chromosomes in the GnomAD database, including 18,131 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 0.45 (18131 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237
• Publications: 8 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.747 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	NM_002336.3	MANE Select	c.1545+1369G>A		intron	N/A	NP_002327.2	O75581
	LRP6	NM_001414244.1		c.1545+1369G>A		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.1545+1369G>A		intron	N/A	NP_001401174.1	O75581

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	ENST00000261349.9	TSL:1 MANE Select	c.1545+1369G>A		intron	N/A	ENSP00000261349.4	O75581
	LRP6	ENST00000543091.1	TSL:1	c.1545+1369G>A		intron	N/A	ENSP00000442472.1	F5H7J9
	LRP6	ENST00000538239.5	TSL:1	n.1137+1369G>A		intron	N/A	ENSP00000445083.1	H0YGW5

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68543 AN: 151854 Hom.: 18143 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.766

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.481

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

GnomAD4 genome AF: 0.451 AC: 68537 AN: 151972 Hom.: 18131 Cov.: 32 AF XY: 0.465 AC XY: 34534 AN XY: 74296

African (AFR) AF: 0.162 AC: 6698 AN: 41454

American (AMR) AF: 0.544 AC: 8315 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1796 AN: 3466

East Asian (EAS) AF: 0.767 AC: 3977 AN: 5188

South Asian (SAS) AF: 0.654 AC: 3154 AN: 4822

European-Finnish (FIN) AF: 0.628 AC: 6618 AN: 10540

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.536 AC: 36421 AN: 67908

Other (OTH) AF: 0.482 AC: 1017 AN: 2108

Alfa AF: 0.450 Hom.: 6352

Bravo AF: 0.430

Asia WGS AF: 0.663 AC: 2301 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.3
DANN	Benign	0.88
PhyloP100		-0.24
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: rs2417085; hg19: chr12-12331375;