rs2304182

Variant names:

• chr19-11128201-G-A
• rs2304182
• NM_000527.5:c.2389+116G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11128201-G-A
• chr19-11128201-G-C
• chr19-11128201-G-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.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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 3 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=-0.86).
• 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2389+116G>A		intron_variant	Intron 16 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2389+116G>A		intron_variant	Intron 16 of 17	1	NM_000527.5	ENSP00000454071.1

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

African (AFR) AF: 0.226 AC: 4531 AN: 20012

American (AMR) AF: 0.0897 AC: 3572 AN: 39840

Ashkenazi Jewish (ASJ) AF: 0.0995 AC: 2089 AN: 21000

East Asian (EAS) AF: 0.323 AC: 11554 AN: 35740

South Asian (SAS) AF: 0.150 AC: 10655 AN: 70804

European-Finnish (FIN) AF: 0.0621 AC: 2558 AN: 41174

Middle Eastern (MID) AF: 0.0968 AC: 301 AN: 3108

European-Non Finnish (NFE) AF: 0.0671 AC: 33494 AN: 499352

Other (OTH) AF: 0.0940 AC: 3534 AN: 37588

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

African (AFR) AF: 0.223 AC: 9237 AN: 41412

American (AMR) AF: 0.0796 AC: 1214 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 377 AN: 3472

East Asian (EAS) AF: 0.311 AC: 1593 AN: 5128

South Asian (SAS) AF: 0.156 AC: 749 AN: 4794

European-Finnish (FIN) AF: 0.0566 AC: 600 AN: 10598

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0707 AC: 4803 AN: 67946

Other (OTH) AF: 0.111 AC: 234 AN: 2108

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
PhyloP100		-0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs2304182; hg19: chr19-11238877;