NM_002336.3:c.3397+531C>T

Variant names:

• chr12-12146835-G-A
• rs11054704
• NM_002336.3:c.3397+531C>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.3397+531C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 152,272 control chromosomes in the GnomAD database, including 1,232 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 0.12 (1232 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370
• Publications: 13 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 (NFE) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.3397+531C>T		intron_variant	Intron 15 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.3397+531C>T		intron_variant	Intron 15 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.3397+531C>T		intron_variant	Intron 15 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.2989+531C>T		intron_variant	Intron 14 of 23	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*24+7856G>A		intron_variant	Intron 5 of 6	2		ENSP00000298566.1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17720 AN: 152154 Hom.: 1231 Cov.: 32

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.0838

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0631

Gnomad SAS AF: 0.0979

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.118

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

GnomAD4 genome AF: 0.116 AC: 17736 AN: 152272 Hom.: 1232 Cov.: 32 AF XY: 0.115 AC XY: 8599 AN XY: 74454

African (AFR) AF: 0.0622 AC: 2584 AN: 41574

American (AMR) AF: 0.0837 AC: 1281 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 403 AN: 3472

East Asian (EAS) AF: 0.0633 AC: 328 AN: 5184

South Asian (SAS) AF: 0.0986 AC: 475 AN: 4818

European-Finnish (FIN) AF: 0.172 AC: 1822 AN: 10608

Middle Eastern (MID) AF: 0.164 AC: 48 AN: 292

European-Non Finnish (NFE) AF: 0.152 AC: 10331 AN: 67996

Other (OTH) AF: 0.117 AC: 248 AN: 2114

Alfa AF: 0.139 Hom.: 2252

Bravo AF: 0.108

Asia WGS AF: 0.0820 AC: 287 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	3.2
DANN	Benign	0.77
PhyloP100		0.037
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: rs11054704; hg19: chr12-12299769;