rs2569540

Variant names:

• chr19-11127563-C-G
• rs2569540
• NM_000527.5:c.2312-445C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11127563-C-G
• chr19-11127563-C-T

Variant summary

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

The NM_000527.5(LDLR):​c.2312-445C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 232,324 control chromosomes in the GnomAD database, including 59,984 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 0.69 (37176 hom., cov: 30)
  • Exomes 𝑓: 0.75 (22808 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.414
• Publications: 10 publications found

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. 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
	LDLR	NM_000527.5	MANE Select	c.2312-445C>G		intron	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.2312-445C>G		intron	N/A	NP_001182727.1
	LDLR	NM_001195799.2		c.2189-445C>G		intron	N/A	NP_001182728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2312-445C>G		intron	N/A	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2570-445C>G		intron	N/A	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2312-445C>G		intron	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104486 AN: 151790 Hom.: 37179 Cov.: 30

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.746

Gnomad ASJ AF: 0.720

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.703

GnomAD4 exome AF: 0.747 AC: 60093 AN: 80416 Hom.: 22808 Cov.: 0 AF XY: 0.742 AC XY: 31373 AN XY: 42284

African (AFR) AF: 0.478 AC: 1323 AN: 2766

American (AMR) AF: 0.755 AC: 3180 AN: 4212

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 1308 AN: 1790

East Asian (EAS) AF: 0.879 AC: 3706 AN: 4218

South Asian (SAS) AF: 0.703 AC: 8657 AN: 12308

European-Finnish (FIN) AF: 0.761 AC: 2506 AN: 3292

Middle Eastern (MID) AF: 0.691 AC: 195 AN: 282

European-Non Finnish (NFE) AF: 0.763 AC: 36216 AN: 47472

Other (OTH) AF: 0.737 AC: 3002 AN: 4076

GnomAD4 genome AF: 0.688 AC: 104524 AN: 151908 Hom.: 37176 Cov.: 30 AF XY: 0.691 AC XY: 51315 AN XY: 74252

African (AFR) AF: 0.489 AC: 20245 AN: 41386

American (AMR) AF: 0.746 AC: 11362 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 2501 AN: 3472

East Asian (EAS) AF: 0.884 AC: 4558 AN: 5156

South Asian (SAS) AF: 0.730 AC: 3522 AN: 4822

European-Finnish (FIN) AF: 0.776 AC: 8188 AN: 10550

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51840 AN: 67978

Other (OTH) AF: 0.701 AC: 1481 AN: 2112

Alfa AF: 0.719 Hom.: 4969

Bravo AF: 0.678

Asia WGS AF: 0.740 AC: 2574 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.43
PhyloP100		-0.41
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: rs2569540; hg19: chr19-11238239;