rs2306692

Variant names:

• chr12-57147482-C-T
• rs2306692
• NM_002332.3:c.841+1992C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002332.3(LRP1):​c.841+1992C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,144 control chromosomes in the GnomAD database, including 2,860 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2857 hom., cov: 32)
  • Exomes 𝑓: 0.13 (3 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 9 publications found

Genes affected

LRP1 (HGNC:6692): (LDL receptor related protein 1) This gene encodes a member of the low-density lipoprotein receptor family of proteins. The encoded preproprotein is proteolytically processed by furin to generate 515 kDa and 85 kDa subunits that form the mature receptor (PMID: 8546712). This receptor is involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the alpha 2-macroglobulin-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients. Expression of this gene decreases with age and has been found to be lower than controls in brain tissue from Alzheimer's disease patients. [provided by RefSeq, Oct 2015]

LRP1-AS (HGNC:51694): (LRP1 antisense RNA)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002332.3. 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
	LRP1	NM_002332.3	MANE Select	c.841+1992C>T		intron	N/A	NP_002323.2	Q07954-1
	LRP1-AS	NR_131938.2	MANE Select	n.138G>A		non_coding_transcript_exon	Exon 1 of 2
	LRP1-AS	NR_131939.2		n.138G>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	ENST00000243077.8	TSL:1 MANE Select	c.841+1992C>T		intron	N/A	ENSP00000243077.3	Q07954-1
	LRP1	ENST00000554174.1	TSL:1	c.841+1992C>T		intron	N/A	ENSP00000451737.1	Q6PJ72
	LRP1	ENST00000553277.5	TSL:1	c.841+1992C>T		intron	N/A	ENSP00000451449.1	Q7Z7K9

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27671 AN: 151878 Hom.: 2851 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.128 AC: 19 AN: 148 Hom.: 3 Cov.: 0 AF XY: 0.102 AC XY: 11 AN XY: 108

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.111 AC: 14 AN: 126

Other (OTH) AF: 0.300 AC: 3 AN: 10

GnomAD4 genome AF: 0.182 AC: 27707 AN: 151996 Hom.: 2857 Cov.: 32 AF XY: 0.184 AC XY: 13670 AN XY: 74314

African (AFR) AF: 0.245 AC: 10171 AN: 41440

American (AMR) AF: 0.213 AC: 3254 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3470

East Asian (EAS) AF: 0.341 AC: 1758 AN: 5148

South Asian (SAS) AF: 0.128 AC: 615 AN: 4820

European-Finnish (FIN) AF: 0.163 AC: 1728 AN: 10600

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9265 AN: 67920

Other (OTH) AF: 0.189 AC: 399 AN: 2116

Alfa AF: 0.150 Hom.: 2169

Bravo AF: 0.187

Asia WGS AF: 0.251 AC: 875 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.1
DANN	Benign	0.68
PhyloP100		-1.1
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2306692;

hg19: chr12-57541265;