rs12313200

Variant names:

• chr12-12131656-G-A
• rs12313200
• NM_002336.3:c.3970+165C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002336.3(LRP6):​c.3970+165C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 152,114 control chromosomes in the GnomAD database, including 1,545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.13 (1545 hom., cov: 31)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.18
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-12131656-G-A is Benign according to our data. Variant chr12-12131656-G-A is described in ClinVar as Benign. ClinVar VariationId is 1229993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.3970+165C>T		intron_variant	Intron 18 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.3970+165C>T		intron_variant	Intron 18 of 22	1	NM_002336.3	ENSP00000261349.4

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20211 AN: 151996 Hom.: 1548 Cov.: 31

Gnomad AFR AF: 0.0839

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.0626

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.163

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

GnomAD4 genome AF: 0.133 AC: 20220 AN: 152114 Hom.: 1545 Cov.: 31 AF XY: 0.132 AC XY: 9837 AN XY: 74376

African (AFR) AF: 0.0840 AC: 3483 AN: 41480

American (AMR) AF: 0.162 AC: 2478 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 721 AN: 3472

East Asian (EAS) AF: 0.0194 AC: 101 AN: 5194

South Asian (SAS) AF: 0.0639 AC: 308 AN: 4818

European-Finnish (FIN) AF: 0.154 AC: 1631 AN: 10566

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10971 AN: 67990

Other (OTH) AF: 0.162 AC: 341 AN: 2110

Alfa AF: 0.146 Hom.: 704

Bravo AF: 0.134

Asia WGS AF: 0.0440 AC: 156 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	12
DANN	Benign	0.19
PhyloP100		1.2
PromoterAI		0.019	Neutral
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: rs12313200; hg19: chr12-12284590;