12-12121384-G-T

Position:

• chr12-12121384-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002336.3(LRP6):​c.4584C>A​(p.Pro1528=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000492 in 1,613,958 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00048 (3 hom.)
• Consequence: LRP6 NM_002336.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.769

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-12121384-G-T is Benign according to our data. Variant chr12-12121384-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1598729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.769 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000578 (88/152118) while in subpopulation AMR AF= 0.000196 (3/15272). AF 95% confidence interval is 0.0000905. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP6	NM_002336.3	c.4584C>A	p.Pro1528=	synonymous_variant	23/23	ENST00000261349.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP6	ENST00000261349.9	c.4584C>A	p.Pro1528=	synonymous_variant	23/23	1	NM_002336.3	P1

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000918 AC: 229 AN: 249422 Hom.: 3 AF XY: 0.000896 AC XY: 121 AN XY: 135008

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000260

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000483 AC: 706 AN: 1461840 Hom.: 3 Cov.: 31 AF XY: 0.000496 AC XY: 361 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.0172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.000565 AC XY: 42 AN XY: 74314

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.000593

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	LRP6: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.5
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs145639537; hg19: chr12-12274318;