12-57173979-C-T

Variant names:

• chr12-57173979-C-T
• rs1800194
• NM_002332.3:c.3546C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002332.3(LRP1):​c.3546C>T​(p.Cys1182Cys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,613,108 control chromosomes in the GnomAD database, including 89,197 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11279 hom., cov: 33)
  • Exomes 𝑓: 0.32 (77918 hom.)
• Consequence: LRP1 NM_002332.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0007581
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.348
• Publications: 25 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 Gene-Disease associations (from GenCC):

• keratosis follicularis spinulosa decalvans

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrophoderma vermiculata

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• developmental dysplasia of the hip 3

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• keratosis pilaris atrophicans

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-57173979-C-T is Benign according to our data. Variant chr12-57173979-C-T is described in ClinVar as Benign. ClinVar VariationId is 1226322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.348 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.479 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	NM_002332.3	MANE Select	c.3546C>T	p.Cys1182Cys	splice_region synonymous	Exon 22 of 89	NP_002323.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	ENST00000243077.8	TSL:1 MANE Select	c.3546C>T	p.Cys1182Cys	splice_region synonymous	Exon 22 of 89	ENSP00000243077.3

Frequencies

GnomAD3 genomes AF: 0.375 AC: 57025 AN: 151936 Hom.: 11253 Cov.: 33

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.366

GnomAD2 exomes AF: 0.355 AC: 88789 AN: 250136 AF XY: 0.337

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.512

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.390

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.318

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.321 AC: 468503 AN: 1461054 Hom.: 77918 Cov.: 40 AF XY: 0.315 AC XY: 228846 AN XY: 726860

African (AFR) AF: 0.485 AC: 16237 AN: 33462

American (AMR) AF: 0.500 AC: 22309 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 7932 AN: 26130

East Asian (EAS) AF: 0.362 AC: 14352 AN: 39682

South Asian (SAS) AF: 0.211 AC: 18177 AN: 86238

European-Finnish (FIN) AF: 0.400 AC: 21273 AN: 53178

Middle Eastern (MID) AF: 0.328 AC: 1880 AN: 5736

European-Non Finnish (NFE) AF: 0.312 AC: 346735 AN: 1111634

Other (OTH) AF: 0.325 AC: 19608 AN: 60356

GnomAD4 genome AF: 0.375 AC: 57090 AN: 152054 Hom.: 11279 Cov.: 33 AF XY: 0.374 AC XY: 27800 AN XY: 74314

African (AFR) AF: 0.485 AC: 20113 AN: 41470

American (AMR) AF: 0.393 AC: 6006 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1076 AN: 3470

East Asian (EAS) AF: 0.398 AC: 2052 AN: 5160

South Asian (SAS) AF: 0.230 AC: 1108 AN: 4824

European-Finnish (FIN) AF: 0.394 AC: 4167 AN: 10576

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21322 AN: 67952

Other (OTH) AF: 0.362 AC: 761 AN: 2104

Alfa AF: 0.315 Hom.: 19123

Bravo AF: 0.391

Asia WGS AF: 0.372 AC: 1294 AN: 3478

EpiCase AF: 0.303

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12732394)

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.78
PhyloP100		-0.35
Mutation Taster		=48/52	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00076
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.040		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: rs1800194; hg19: chr12-57567762; COSMIC: COSV54518846; COSMIC: COSV54518846;