12-12149950-A-G

Variant names:

• chr12-12149950-A-G
• rs11054710
• NM_002336.3:c.2995-797T>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.2995-797T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 152,194 control chromosomes in the GnomAD database, including 513 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 0.075 (513 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.152
• Publications: 5 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.2995-797T>C		intron_variant	Intron 13 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.2995-797T>C		intron_variant	Intron 13 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.2995-797T>C		intron_variant	Intron 13 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.2587-797T>C		intron_variant	Intron 12 of 23	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*24+10971A>G		intron_variant	Intron 5 of 6	2		ENSP00000298566.1

Frequencies

GnomAD3 genomes AF: 0.0752 AC: 11438 AN: 152076 Hom.: 513 Cov.: 32

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0876

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0396

Gnomad FIN AF: 0.0732

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0924

Gnomad OTH AF: 0.0868

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

GnomAD4 genome AF: 0.0751 AC: 11437 AN: 152194 Hom.: 513 Cov.: 32 AF XY: 0.0742 AC XY: 5524 AN XY: 74414

African (AFR) AF: 0.0450 AC: 1870 AN: 41518

American (AMR) AF: 0.113 AC: 1724 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0876 AC: 304 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5188

South Asian (SAS) AF: 0.0401 AC: 193 AN: 4818

European-Finnish (FIN) AF: 0.0732 AC: 775 AN: 10582

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0924 AC: 6282 AN: 68006

Other (OTH) AF: 0.0859 AC: 181 AN: 2108

Alfa AF: 0.0575 Hom.: 84

Bravo AF: 0.0773

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.72
DANN	Benign	0.37
PhyloP100		-0.15
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: rs11054710; hg19: chr12-12302884;