12-12180418-C-T

Variant names:

• chr12-12180418-C-T
• rs10492120
• NM_002336.3:c.1374-437G>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.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
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002336.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	NM_002336.3	MANE Select	c.1374-437G>A		intron	N/A	NP_002327.2	O75581
	LRP6	NM_001414244.1		c.1374-437G>A		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.1374-437G>A		intron	N/A	NP_001401174.1	O75581

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	ENST00000261349.9	TSL:1 MANE Select	c.1374-437G>A		intron	N/A	ENSP00000261349.4	O75581
	LRP6	ENST00000543091.1	TSL:1	c.1374-437G>A		intron	N/A	ENSP00000442472.1	F5H7J9
	LRP6	ENST00000538239.5	TSL:1	n.966-437G>A		intron	N/A	ENSP00000445083.1	H0YGW5

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

African (AFR) AF: 0.435 AC: 17975 AN: 41350

American (AMR) AF: 0.678 AC: 10329 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2114 AN: 3466

East Asian (EAS) AF: 0.772 AC: 3996 AN: 5176

South Asian (SAS) AF: 0.692 AC: 3336 AN: 4818

European-Finnish (FIN) AF: 0.697 AC: 7310 AN: 10492

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.630 AC: 42749 AN: 67886

Other (OTH) AF: 0.621 AC: 1308 AN: 2106

Alfa AF: 0.611 Hom.: 47861

Bravo AF: 0.583

Asia WGS AF: 0.706 AC: 2452 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.69
PhyloP100		-0.88
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: rs10492120; hg19: chr12-12333352;