12-12203966-A-G

Variant names:

• chr12-12203966-A-G
• rs6488507
• NM_002336.3:c.450-566T>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.450-566T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 151,932 control chromosomes in the GnomAD database, including 16,770 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 0.46 (16770 hom., cov: 31)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280
• 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]

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 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.450-566T>C		intron	N/A	NP_002327.2
	LRP6	NM_001414244.1		c.450-566T>C		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.450-566T>C		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.450-566T>C		intron	N/A	ENSP00000261349.4
	LRP6	ENST00000543091.1	TSL:1	c.450-566T>C		intron	N/A	ENSP00000442472.1
	LRP6	ENST00000538239.5	TSL:1	n.42-566T>C		intron	N/A	ENSP00000445083.1

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69323 AN: 151814 Hom.: 16781 Cov.: 31

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.458

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

GnomAD4 genome AF: 0.456 AC: 69338 AN: 151932 Hom.: 16770 Cov.: 31 AF XY: 0.468 AC XY: 34778 AN XY: 74240

African (AFR) AF: 0.308 AC: 12792 AN: 41476

American (AMR) AF: 0.525 AC: 8004 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1533 AN: 3466

East Asian (EAS) AF: 0.759 AC: 3914 AN: 5156

South Asian (SAS) AF: 0.624 AC: 3003 AN: 4814

European-Finnish (FIN) AF: 0.572 AC: 6023 AN: 10528

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.480 AC: 32633 AN: 67920

Other (OTH) AF: 0.460 AC: 969 AN: 2108

Alfa AF: 0.467 Hom.: 6599

Bravo AF: 0.444

Asia WGS AF: 0.651 AC: 2261 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.0
DANN	Benign	0.72
PhyloP100		-0.028
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: rs6488507; hg19: chr12-12356900;