rs2304182

Positions:

• chr19-11128201-G-A
• chr19-11128201-G-C
• chr19-11128201-G-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.2389+116G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0992 in 920,526 control chromosomes in the GnomAD database, including 6,707 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1667 hom., cov: 30)
  • Exomes 𝑓: 0.094 (5040 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.263

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=-0.86).
• BP6: Variant 19-11128201-G-A is Benign according to our data. Variant chr19-11128201-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2389+116G>A		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2389+116G>A		intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18966 AN: 151790 Hom.: 1661 Cov.: 30

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.0798

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0566

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0707

Gnomad OTH AF: 0.110

GnomAD4 exome AF: 0.0940 AC: 72288 AN: 768618 Hom.: 5040 AF XY: 0.0966 AC XY: 39129 AN XY: 405234

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.0897

Gnomad4 ASJ exome AF: 0.0995

Gnomad4 EAS exome AF: 0.323

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.0621

Gnomad4 NFE exome AF: 0.0671

Gnomad4 OTH exome AF: 0.0940

GnomAD4 genome AF: 0.125 AC: 19001 AN: 151908 Hom.: 1667 Cov.: 30 AF XY: 0.125 AC XY: 9280 AN XY: 74226

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.0796

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.311

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.0566

Gnomad4 NFE AF: 0.0707

Gnomad4 OTH AF: 0.111

Alfa AF: 0.0413 Hom.: 32

Bravo AF: 0.131

Asia WGS AF: 0.185 AC: 646 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs2304182; hg19: chr19-11238877;