chr12-12164494-G-A

Position:

• chr12-12164494-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2 PP3_Moderate PP5_Moderate BS2

The NM_002336.3(LRP6):​c.1831C>T​(p.Arg611Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: LRP6 NM_002336.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.03

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]

LRP6 (HGNC:):

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 Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP6. . Gene score misZ 2.7541 (greater than the threshold 3.09). Trascript score misZ 4.2572 (greater than threshold 3.09). GenCC has associacion of gene with coronary artery disease, autosomal dominant 2, tooth agenesis, selective, 7, tooth agenesis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 12-12164494-G-A is Pathogenic according to our data. Variant chr12-12164494-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6267.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-12164494-G-A is described in UniProt as null.
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP6	NM_002336.3	c.1831C>T	p.Arg611Cys	missense_variant	9/23	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.1831C>T	p.Arg611Cys	missense_variant	9/23	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.1831C>T	p.Arg611Cys	missense_variant	9/23	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.1423C>T		non_coding_transcript_exon_variant	8/24	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.*25-22811G>A		intron_variant		2		ENSP00000298566.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251374 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Coronary artery disease, autosomal dominant 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 02, 2007

- -

LRP6-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2023

The LRP6 c.1831C>T variant is predicted to result in the amino acid substitution p.Arg611Cys. This variant has been reported in the heterozygous state in multiple individuals from two separate families with early-onset coronary artery disease with some also having metabolic risk factors (Mani et al 2007. PubMed ID: 17332414; Guo et al. 2016. PubMed ID: 27455246). Of note, in one of the families noted above this variant was reported in the homozygous state (Mani et al 2007. PubMed ID: 17332414). Functional studies have shown that this variant impacts protein function (Liu et al. 2008. PubMed ID: 18948618; Keramati et al. 2011. PubMed ID: 21245321; Guo et al. 2016. PubMed ID: 27455246). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-12317428-G-A). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.029	D;D
Sift4G	Benign	0.20	T;T
Polyphen		0.99	D;D
Vest4		0.67
MutPred		0.87		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.94
MPC		1.3
ClinPred		0.64	D
GERP RS		5.7
Varity_R		0.64
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918313; hg19: chr12-12317428; COSMIC: COSV53793011;