12-12170684-C-G

Variant names:

• chr12-12170684-C-G
• rs7294695
• NM_002336.3:c.1546-5389G>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.1546-5389G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 151,444 control chromosomes in the GnomAD database, including 15,762 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 0.43 (15762 hom., cov: 28)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.241
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.1546-5389G>C		intron_variant	Intron 7 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.1546-5389G>C		intron_variant	Intron 7 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.1546-5389G>C		intron_variant	Intron 7 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.1138-5389G>C		intron_variant	Intron 6 of 23	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*25-16621C>G		intron_variant	Intron 5 of 6	2		ENSP00000298566.1

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65644 AN: 151326 Hom.: 15770 Cov.: 28

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.435

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

GnomAD4 genome AF: 0.433 AC: 65642 AN: 151444 Hom.: 15762 Cov.: 28 AF XY: 0.446 AC XY: 32982 AN XY: 73970

African (AFR) AF: 0.238 AC: 9798 AN: 41224

American (AMR) AF: 0.514 AC: 7809 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1515 AN: 3468

East Asian (EAS) AF: 0.807 AC: 4156 AN: 5148

South Asian (SAS) AF: 0.630 AC: 3018 AN: 4790

European-Finnish (FIN) AF: 0.548 AC: 5739 AN: 10464

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

European-Non Finnish (NFE) AF: 0.475 AC: 32238 AN: 67846

Other (OTH) AF: 0.437 AC: 918 AN: 2100

Alfa AF: 0.436 Hom.: 1966

Bravo AF: 0.419

Asia WGS AF: 0.671 AC: 2333 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.67
PhyloP100		-0.24
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: rs7294695; hg19: chr12-12323618;