12-12180418-C-T

Position:

• chr12-12180418-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002336.3(LRP6):​c.1374-437G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 151,728 control chromosomes in the GnomAD database, including 27,343 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 0.59 (27343 hom., cov: 29)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.875

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]

LRP6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP6	NM_002336.3	c.1374-437G>A		intron_variant		ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.1374-437G>A		intron_variant		1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.1374-437G>A		intron_variant		1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.966-437G>A		intron_variant		1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*25-6887C>T		intron_variant		2		ENSP00000298566.1

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89755 AN: 151610 Hom.: 27345 Cov.: 29

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.693

Gnomad FIN AF: 0.697

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.630

Gnomad OTH AF: 0.620

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

GnomAD4 genome AF: 0.592 AC: 89791 AN: 151728 Hom.: 27343 Cov.: 29 AF XY: 0.602 AC XY: 44680 AN XY: 74164

Gnomad4 AFR AF: 0.435

Gnomad4 AMR AF: 0.678

Gnomad4 ASJ AF: 0.610

Gnomad4 EAS AF: 0.772

Gnomad4 SAS AF: 0.692

Gnomad4 FIN AF: 0.697

Gnomad4 NFE AF: 0.630

Gnomad4 OTH AF: 0.621

Alfa AF: 0.591 Hom.: 7048

Bravo AF: 0.583

Asia WGS AF: 0.706 AC: 2452 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.69

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: rs10492120; hg19: chr12-12333352;