12-12126427-G-A

Variant names:

• chr12-12126427-G-A
• rs4477532
• NM_002336.3:c.4312+264C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002336.3(LRP6):​c.4312+264C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 152,094 control chromosomes in the GnomAD database, including 15,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.43 (15678 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-12126427-G-A is Benign according to our data. Variant chr12-12126427-G-A is described in ClinVar as Benign. ClinVar VariationId is 1238981.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 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.4312+264C>T		intron	N/A	NP_002327.2
	LRP6	NM_001414244.1		c.4405+264C>T		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.4312+264C>T		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.4312+264C>T		intron	N/A	ENSP00000261349.4
	LRP6	ENST00000543091.1	TSL:1	c.4177+264C>T		intron	N/A	ENSP00000442472.1
	LRP6	ENST00000538239.5	TSL:1	n.3904+264C>T		intron	N/A	ENSP00000445083.1

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65574 AN: 151976 Hom.: 15687 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.433

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

GnomAD4 genome AF: 0.431 AC: 65571 AN: 152094 Hom.: 15678 Cov.: 32 AF XY: 0.444 AC XY: 33006 AN XY: 74356

African (AFR) AF: 0.237 AC: 9819 AN: 41500

American (AMR) AF: 0.512 AC: 7812 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 1460 AN: 3466

East Asian (EAS) AF: 0.804 AC: 4162 AN: 5178

South Asian (SAS) AF: 0.626 AC: 3014 AN: 4812

European-Finnish (FIN) AF: 0.546 AC: 5774 AN: 10578

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32153 AN: 67982

Other (OTH) AF: 0.436 AC: 920 AN: 2112

Alfa AF: 0.463 Hom.: 72440

Bravo AF: 0.417

Asia WGS AF: 0.668 AC: 2322 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.16
DANN	Benign	0.50
PhyloP100		-1.6
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: rs4477532; hg19: chr12-12279361;