12-57209032-C-G

Variant names:

• chr12-57209032-C-G
• rs7956957
• NM_002332.3:c.12146-51C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002332.3(LRP1):​c.12146-51C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 1,469,804 control chromosomes in the GnomAD database, including 297,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23674 hom., cov: 32)
  • Exomes 𝑓: 0.64 (274021 hom.)
• Consequence: LRP1 NM_002332.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.153
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-57209032-C-G is Benign according to our data. Variant chr12-57209032-C-G is described in ClinVar as Benign. ClinVar VariationId is 1263181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3	c.12146-51C>G		intron_variant	Intron 78 of 88	ENST00000243077.8	NP_002323.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8	c.12146-51C>G		intron_variant	Intron 78 of 88	1	NM_002332.3	ENSP00000243077.3
LRP1	ENST00000556356.1	n.2840-51C>G		intron_variant	Intron 6 of 16	2

Frequencies

GnomAD3 genomes AF: 0.534 AC: 81088 AN: 151922 Hom.: 23670 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.555

GnomAD2 exomes AF: 0.592 AC: 144861 AN: 244816 AF XY: 0.614

Gnomad AFR exome AF: 0.273

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.630

Gnomad EAS exome AF: 0.525

Gnomad FIN exome AF: 0.580

Gnomad NFE exome AF: 0.647

Gnomad OTH exome AF: 0.616

GnomAD4 exome AF: 0.639 AC: 841972 AN: 1317764 Hom.: 274021 Cov.: 18 AF XY: 0.646 AC XY: 424849 AN XY: 657838

African (AFR) AF: 0.265 AC: 8091 AN: 30556

American (AMR) AF: 0.453 AC: 19713 AN: 43550

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 15676 AN: 24782

East Asian (EAS) AF: 0.575 AC: 22196 AN: 38582

South Asian (SAS) AF: 0.760 AC: 62764 AN: 82630

European-Finnish (FIN) AF: 0.584 AC: 30809 AN: 52754

Middle Eastern (MID) AF: 0.593 AC: 3019 AN: 5090

European-Non Finnish (NFE) AF: 0.655 AC: 645476 AN: 984782

Other (OTH) AF: 0.622 AC: 34228 AN: 55038

GnomAD4 genome AF: 0.533 AC: 81101 AN: 152040 Hom.: 23674 Cov.: 32 AF XY: 0.536 AC XY: 39819 AN XY: 74320

African (AFR) AF: 0.283 AC: 11753 AN: 41466

American (AMR) AF: 0.549 AC: 8399 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2176 AN: 3470

East Asian (EAS) AF: 0.526 AC: 2713 AN: 5162

South Asian (SAS) AF: 0.747 AC: 3600 AN: 4820

European-Finnish (FIN) AF: 0.592 AC: 6252 AN: 10560

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.652 AC: 44315 AN: 67952

Other (OTH) AF: 0.557 AC: 1176 AN: 2112

Alfa AF: 0.545 Hom.: 3390

Bravo AF: 0.507

Asia WGS AF: 0.556 AC: 1936 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.86
DANN	Benign	0.43
PhyloP100		-0.15
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

Other links and lift over

dbSNP: rs7956957; hg19: chr12-57602815; COSMIC: COSV54515707; COSMIC: COSV54515707;