12-12209506-C-T

Variant names:

• chr12-12209506-C-T
• rs10466849
• NM_002336.3:c.450-6106G>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.450-6106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 151,774 control chromosomes in the GnomAD database, including 3,173 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 0.19 (3173 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.74
• Publications: 4 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 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.450-6106G>A		intron	N/A	NP_002327.2	O75581
	LRP6	NM_001414244.1		c.450-6106G>A		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.450-6106G>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.450-6106G>A		intron	N/A	ENSP00000261349.4	O75581
	LRP6	ENST00000543091.1	TSL:1	c.450-6106G>A		intron	N/A	ENSP00000442472.1	F5H7J9
	LRP6	ENST00000538239.5	TSL:1	n.42-6106G>A		intron	N/A	ENSP00000445083.1	H0YGW5

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28378 AN: 151656 Hom.: 3165 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.0215

Gnomad SAS AF: 0.0597

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.200

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

GnomAD4 genome AF: 0.187 AC: 28420 AN: 151774 Hom.: 3173 Cov.: 32 AF XY: 0.184 AC XY: 13621 AN XY: 74186

African (AFR) AF: 0.308 AC: 12753 AN: 41380

American (AMR) AF: 0.171 AC: 2605 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 581 AN: 3466

East Asian (EAS) AF: 0.0217 AC: 112 AN: 5162

South Asian (SAS) AF: 0.0608 AC: 293 AN: 4822

European-Finnish (FIN) AF: 0.124 AC: 1300 AN: 10480

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10145 AN: 67892

Other (OTH) AF: 0.199 AC: 419 AN: 2108

Alfa AF: 0.147 Hom.: 767

Bravo AF: 0.199

Asia WGS AF: 0.0620 AC: 216 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.5
DANN	Benign	0.30
PhyloP100		-1.7
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: rs10466849; hg19: chr12-12362440;