rs7957531

Variant names:

• chr12-12178604-A-G
• rs7957531
• NM_002336.3:c.1545+1206T>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.1545+1206T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,174 control chromosomes in the GnomAD database, including 2,145 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 0.14 (2145 hom., cov: 32)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07
• Publications: 4 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.1545+1206T>C		intron_variant	Intron 7 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.1545+1206T>C		intron_variant	Intron 7 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.1545+1206T>C		intron_variant	Intron 7 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.1137+1206T>C		intron_variant	Intron 6 of 23	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*25-8701A>G		intron_variant	Intron 5 of 6	2		ENSP00000298566.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21622 AN: 152056 Hom.: 2135 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0918

Gnomad EAS AF: 0.00481

Gnomad SAS AF: 0.0372

Gnomad FIN AF: 0.0680

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0932

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.142 AC: 21660 AN: 152174 Hom.: 2145 Cov.: 32 AF XY: 0.139 AC XY: 10365 AN XY: 74420

African (AFR) AF: 0.279 AC: 11587 AN: 41470

American (AMR) AF: 0.134 AC: 2054 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0918 AC: 318 AN: 3464

East Asian (EAS) AF: 0.00482 AC: 25 AN: 5186

South Asian (SAS) AF: 0.0377 AC: 182 AN: 4834

European-Finnish (FIN) AF: 0.0680 AC: 722 AN: 10618

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0932 AC: 6339 AN: 67986

Other (OTH) AF: 0.140 AC: 296 AN: 2110

Alfa AF: 0.122 Hom.: 565

Bravo AF: 0.154

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	16
DANN	Benign	0.73
PhyloP100		2.1
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: rs7957531; hg19: chr12-12331538;