chr12-12126427-G-A

Position:

• chr12-12126427-G-A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP6	NM_002336.3	c.4312+264C>T		intron_variant		ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.4312+264C>T		intron_variant		1	NM_002336.3	ENSP00000261349	P1

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

Gnomad4 AFR AF: 0.237

Gnomad4 AMR AF: 0.512

Gnomad4 ASJ AF: 0.421

Gnomad4 EAS AF: 0.804

Gnomad4 SAS AF: 0.626

Gnomad4 FIN AF: 0.546

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.436

Alfa AF: 0.469 Hom.: 34913

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.16
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs4477532; hg19: chr12-12279361;