rs7975614

Variant names:

• chr12-12179908-C-T
• rs7975614
• NM_002336.3:c.1447G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-12179908-C-T
• chr12-12179908-C-A

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.1447G>A​(p.Val483Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00981 in 1,613,926 control chromosomes in the GnomAD database, including 1,384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (705 hom., cov: 31)
  • Exomes 𝑓: 0.0054 (679 hom.)
• Consequence: LRP6 NM_002336.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.06
• Publications: 14 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 (MetaRNN=0.0018368661).
• BP6: Variant 12-12179908-C-T is Benign according to our data. Variant chr12-12179908-C-T is described in ClinVar as Benign. ClinVar VariationId is 1221930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	NM_002336.3	MANE Select	c.1447G>A	p.Val483Ile	missense	Exon 7 of 23	NP_002327.2	O75581
	LRP6	NM_001414244.1		c.1447G>A	p.Val483Ile	missense	Exon 7 of 24	NP_001401173.1
	LRP6	NM_001414245.1		c.1447G>A	p.Val483Ile	missense	Exon 7 of 24	NP_001401174.1	O75581

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP6	ENST00000261349.9	TSL:1 MANE Select	c.1447G>A	p.Val483Ile	missense	Exon 7 of 23	ENSP00000261349.4	O75581
	LRP6	ENST00000543091.1	TSL:1	c.1447G>A	p.Val483Ile	missense	Exon 7 of 23	ENSP00000442472.1	F5H7J9
	LRP6	ENST00000538239.5	TSL:1	n.1039G>A		non_coding_transcript_exon	Exon 6 of 24	ENSP00000445083.1	H0YGW5

Frequencies

GnomAD3 genomes AF: 0.0524 AC: 7968 AN: 152098 Hom.: 706 Cov.: 31

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0133 AC: 3350 AN: 251354 AF XY: 0.00965

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00536 AC: 7835 AN: 1461710 Hom.: 679 Cov.: 32 AF XY: 0.00463 AC XY: 3370 AN XY: 727158

African (AFR) AF: 0.193 AC: 6466 AN: 33468

American (AMR) AF: 0.00850 AC: 380 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000229 AC: 255 AN: 1111886

Other (OTH) AF: 0.0112 AC: 679 AN: 60388

GnomAD4 genome AF: 0.0525 AC: 7991 AN: 152216 Hom.: 705 Cov.: 31 AF XY: 0.0502 AC XY: 3737 AN XY: 74440

African (AFR) AF: 0.183 AC: 7604 AN: 41494

American (AMR) AF: 0.0177 AC: 270 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68012

Other (OTH) AF: 0.0374 AC: 79 AN: 2114

Alfa AF: 0.0217 Hom.: 917

Bravo AF: 0.0598

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.177 AC: 782

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0162 AC: 1967

Asia WGS AF: 0.0110 AC: 41 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	0.042
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.77	N
PhyloP100		5.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.34
Sift	Benign	0.20	T
Sift4G	Benign	0.24	T
Polyphen		0.013	B
Vest4		0.21
MPC		0.47
ClinPred		0.015	T
GERP RS		5.8
Varity_R		0.14
gMVP		0.26
Mutation Taster		=84/16	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: rs7975614; hg19: chr12-12332842;