rs1800154

Variant names:

• chr12-57195876-C-T
• rs1800154
• NM_002332.3:c.8574C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002332.3(LRP1):​c.8574C>T​(p.Cys2858Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,613,318 control chromosomes in the GnomAD database, including 90,318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11613 hom., cov: 33)
  • Exomes 𝑓: 0.32 (78705 hom.)
• Consequence: LRP1 NM_002332.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.69

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]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 12-57195876-C-T is Benign according to our data. Variant chr12-57195876-C-T is described in ClinVar as [Benign]. Clinvar id is 1222429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3	c.8574C>T	p.Cys2858Cys	synonymous_variant	Exon 54 of 89	ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.8574C>T	p.Cys2858Cys	synonymous_variant	Exon 54 of 89	1	NM_002332.3	ENSP00000243077.3

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57754 AN: 151914 Hom.: 11596 Cov.: 33

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.368

GnomAD2 exomes AF: 0.357 AC: 89396 AN: 250394 AF XY: 0.338

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.515

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.397

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.318

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.322 AC: 470705 AN: 1461288 Hom.: 78705 Cov.: 58 AF XY: 0.316 AC XY: 229859 AN XY: 726976

Gnomad4 AFR exome AF: 0.498 AC: 16686 AN: 33480

Gnomad4 AMR exome AF: 0.503 AC: 22497 AN: 44694

Gnomad4 ASJ exome AF: 0.304 AC: 7933 AN: 26136

Gnomad4 EAS exome AF: 0.368 AC: 14605 AN: 39698

Gnomad4 SAS exome AF: 0.212 AC: 18256 AN: 86250

Gnomad4 FIN exome AF: 0.400 AC: 21190 AN: 52972

Gnomad4 NFE exome AF: 0.313 AC: 347931 AN: 1111914

Gnomad4 Remaining exome AF: 0.326 AC: 19711 AN: 60378

GnomAD4 genome AF: 0.380 AC: 57808 AN: 152030 Hom.: 11613 Cov.: 33 AF XY: 0.379 AC XY: 28133 AN XY: 74310

Gnomad4 AFR AF: 0.499 AC: 0.498504 AN: 0.498504

Gnomad4 AMR AF: 0.397 AC: 0.396978 AN: 0.396978

Gnomad4 ASJ AF: 0.310 AC: 0.310196 AN: 0.310196

Gnomad4 EAS AF: 0.407 AC: 0.40735 AN: 0.40735

Gnomad4 SAS AF: 0.230 AC: 0.230178 AN: 0.230178

Gnomad4 FIN AF: 0.393 AC: 0.393323 AN: 0.393323

Gnomad4 NFE AF: 0.315 AC: 0.314549 AN: 0.314549

Gnomad4 OTH AF: 0.365 AC: 0.364544 AN: 0.364544

Alfa AF: 0.340 Hom.: 4724

Bravo AF: 0.397

Asia WGS AF: 0.374 AC: 1301 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.308

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

- -

Keratosis pilaris Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	2.2
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800154; hg19: chr12-57589659; COSMIC: COSV54503099; COSMIC: COSV54503099;