12-12156753-C-T

Variant names:

• chr12-12156753-C-T
• rs11609634
• NM_002336.3:c.2791+2076G>A

Variant summary

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

The NM_002336.3(LRP6):​c.2791+2076G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 152,078 control chromosomes in the GnomAD database, including 14,913 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 0.41 (14913 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.295
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.2791+2076G>A		intron_variant	Intron 12 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.2791+2076G>A		intron_variant	Intron 12 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.2791+2076G>A		intron_variant	Intron 12 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.2383+2076G>A		intron_variant	Intron 11 of 23	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*24+17774C>T		intron_variant	Intron 5 of 6	2		ENSP00000298566.1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61806 AN: 151960 Hom.: 14923 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.416

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

GnomAD4 genome AF: 0.406 AC: 61795 AN: 152078 Hom.: 14913 Cov.: 32 AF XY: 0.419 AC XY: 31160 AN XY: 74344

African (AFR) AF: 0.148 AC: 6134 AN: 41492

American (AMR) AF: 0.502 AC: 7679 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1493 AN: 3472

East Asian (EAS) AF: 0.808 AC: 4183 AN: 5174

South Asian (SAS) AF: 0.626 AC: 3010 AN: 4810

European-Finnish (FIN) AF: 0.546 AC: 5764 AN: 10562

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

European-Non Finnish (NFE) AF: 0.474 AC: 32186 AN: 67964

Other (OTH) AF: 0.419 AC: 887 AN: 2116

Alfa AF: 0.454 Hom.: 27477

Bravo AF: 0.389

Asia WGS AF: 0.663 AC: 2303 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.69
DANN	Benign	0.76
PhyloP100		-0.29
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: rs11609634; hg19: chr12-12309687;