12-12138545-G-C

Variant names:

• chr12-12138545-G-C
• rs2075241
• NM_002336.3:c.3398-11C>G

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.3398-11C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,609,070 control chromosomes in the GnomAD database, including 24,476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2846 hom., cov: 31)
  • Exomes 𝑓: 0.17 (21630 hom.)
• Consequence: LRP6 NM_002336.3 intron
• Scores: Splicing: ADA: 0.01568
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.616
• Publications: 17 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=-0.79).
• BP6: Variant 12-12138545-G-C is Benign according to our data. Variant chr12-12138545-G-C is described in ClinVar as Benign. ClinVar VariationId is 1181344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	NM_002336.3	MANE Select	c.3398-11C>G		intron	N/A	NP_002327.2
	LRP6	NM_001414244.1		c.3491-11C>G		intron	N/A	NP_001401173.1
	LRP6	NM_001414245.1		c.3398-11C>G		intron	N/A	NP_001401174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	ENST00000261349.9	TSL:1 MANE Select	c.3398-11C>G		intron	N/A	ENSP00000261349.4
	LRP6	ENST00000543091.1	TSL:1	c.3398-11C>G		intron	N/A	ENSP00000442472.1
	LRP6	ENST00000538239.5	TSL:1	n.2990-11C>G		intron	N/A	ENSP00000445083.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28551 AN: 151818 Hom.: 2843 Cov.: 31

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.0970

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.180

GnomAD2 exomes AF: 0.175 AC: 43881 AN: 250572 AF XY: 0.175

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.0918

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.168 AC: 245303 AN: 1457134 Hom.: 21630 Cov.: 30 AF XY: 0.170 AC XY: 123038 AN XY: 725248

African (AFR) AF: 0.242 AC: 8081 AN: 33392

American (AMR) AF: 0.205 AC: 9156 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6179 AN: 26102

East Asian (EAS) AF: 0.0914 AC: 3623 AN: 39650

South Asian (SAS) AF: 0.207 AC: 17870 AN: 86134

European-Finnish (FIN) AF: 0.112 AC: 5971 AN: 53390

Middle Eastern (MID) AF: 0.237 AC: 1366 AN: 5752

European-Non Finnish (NFE) AF: 0.165 AC: 182543 AN: 1107764

Other (OTH) AF: 0.175 AC: 10514 AN: 60240

GnomAD4 genome AF: 0.188 AC: 28579 AN: 151936 Hom.: 2846 Cov.: 31 AF XY: 0.183 AC XY: 13614 AN XY: 74254

African (AFR) AF: 0.245 AC: 10120 AN: 41390

American (AMR) AF: 0.177 AC: 2708 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3470

East Asian (EAS) AF: 0.0968 AC: 500 AN: 5164

South Asian (SAS) AF: 0.198 AC: 954 AN: 4816

European-Finnish (FIN) AF: 0.111 AC: 1173 AN: 10558

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11674 AN: 67966

Other (OTH) AF: 0.180 AC: 380 AN: 2108

Alfa AF: 0.185 Hom.: 495

Bravo AF: 0.196

Asia WGS AF: 0.159 AC: 554 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.69
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.016
dbscSNV1_RF	Benign	0.21
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: rs2075241; hg19: chr12-12291479; COSMIC: COSV53786535; COSMIC: COSV53786535;