chr12-12138545-G-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.3398-11C>G		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.3398-11C>G		intron_variant	Intron 15 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.3398-11C>G		intron_variant	Intron 15 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.2990-11C>G		intron_variant	Intron 14 of 23	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.712-291G>C		intron_variant	Intron 4 of 6	2		ENSP00000298566.1

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

GnomAD3 exomes AF: 0.175 AC: 43881 AN: 250572 Hom.: 4144 AF XY: 0.175 AC XY: 23765 AN XY: 135548

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 SAS exome AF: 0.205

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

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.237

Gnomad4 EAS exome AF: 0.0914

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.175

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

Gnomad4 AFR AF: 0.245

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.0968

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.180

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs2075241; hg19: chr12-12291479; COSMIC: COSV53786535; COSMIC: COSV53786535;