rs2569540

chr19-11127563-C-Gchr19-11127563-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. Variant has been reported in Lovd as Benign (no stars).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-11127563-C-G is Benign according to our data. Variant chr19-11127563-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2312-445C>G		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2312-445C>G		intron_variant		1	NM_000527.5	P3

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

Gnomad4 AFR exome AF: 0.478

Gnomad4 AMR exome AF: 0.755

Gnomad4 ASJ exome AF: 0.731

Gnomad4 EAS exome AF: 0.879

Gnomad4 SAS exome AF: 0.703

Gnomad4 FIN exome AF: 0.761

Gnomad4 NFE exome AF: 0.763

Gnomad4 OTH exome AF: 0.737

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

Gnomad4 AFR AF: 0.489

Gnomad4 AMR AF: 0.746

Gnomad4 ASJ AF: 0.720

Gnomad4 EAS AF: 0.884

Gnomad4 SAS AF: 0.730

Gnomad4 FIN AF: 0.776

Gnomad4 NFE AF: 0.763

Gnomad4 OTH AF: 0.701

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.3
Dann	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs2569540; hg19: chr19-11238239;