chr12-12122001-T-C

Variant names:

• chr12-12122001-T-C
• rs2284396
• NM_002336.3:c.4548-581A>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.4548-581A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 152,046 control chromosomes in the GnomAD database, including 16,743 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 (16743 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600
• Publications: 12 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 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.4548-581A>G		intron	N/A	NP_002327.2	O75581
	LRP6	NM_001414244.1		c.4641-581A>G		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.4548-581A>G		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.4548-581A>G		intron	N/A	ENSP00000261349.4	O75581
	LRP6	ENST00000543091.1	TSL:1	c.4413-581A>G		intron	N/A	ENSP00000442472.1	F5H7J9
	LRP6	ENST00000538239.5	TSL:1	n.4140-581A>G		intron	N/A	ENSP00000445083.1	H0YGW5

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69138 AN: 151928 Hom.: 16742 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.457

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

GnomAD4 genome AF: 0.455 AC: 69176 AN: 152046 Hom.: 16743 Cov.: 32 AF XY: 0.466 AC XY: 34621 AN XY: 74318

African (AFR) AF: 0.309 AC: 12829 AN: 41464

American (AMR) AF: 0.521 AC: 7967 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1467 AN: 3472

East Asian (EAS) AF: 0.818 AC: 4240 AN: 5182

South Asian (SAS) AF: 0.631 AC: 3031 AN: 4806

European-Finnish (FIN) AF: 0.546 AC: 5771 AN: 10562

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.477 AC: 32437 AN: 67964

Other (OTH) AF: 0.461 AC: 974 AN: 2112

Alfa AF: 0.478 Hom.: 9711

Bravo AF: 0.445

Asia WGS AF: 0.687 AC: 2388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.8
DANN	Benign	0.77
PhyloP100		0.0060
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: rs2284396; hg19: chr12-12274935; COSMIC: COSV53793285; COSMIC: COSV53793285;