chr12-12197179-G-A

Variant names:

• chr12-12197179-G-A
• rs2417086
• NM_002336.3:c.647+6024C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002336.3(LRP6):​c.647+6024C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 152,034 control chromosomes in the GnomAD database, including 14,923 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 0.40 (14923 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.545
• Publications: 8 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.647+6024C>T		intron_variant	Intron 3 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.647+6024C>T		intron_variant	Intron 3 of 22	1	NM_002336.3	ENSP00000261349.4

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60389 AN: 151916 Hom.: 14935 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.416

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

GnomAD4 genome AF: 0.397 AC: 60382 AN: 152034 Hom.: 14923 Cov.: 32 AF XY: 0.411 AC XY: 30569 AN XY: 74298

African (AFR) AF: 0.101 AC: 4172 AN: 41464

American (AMR) AF: 0.504 AC: 7710 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1532 AN: 3466

East Asian (EAS) AF: 0.763 AC: 3950 AN: 5178

South Asian (SAS) AF: 0.631 AC: 3041 AN: 4818

European-Finnish (FIN) AF: 0.573 AC: 6043 AN: 10546

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.480 AC: 32587 AN: 67960

Other (OTH) AF: 0.419 AC: 884 AN: 2110

Alfa AF: 0.449 Hom.: 52203

Bravo AF: 0.375

Asia WGS AF: 0.646 AC: 2244 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.9
DANN	Benign	0.54
PhyloP100		-0.55
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: rs2417086; hg19: chr12-12350113;