rs2738450

Variant names:

• chr19-11118289-C-A
• rs2738450
• NM_000527.5:c.1845+1291C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11118289-C-A
• chr19-11118289-C-G

Variant summary

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

The NM_000527.5(LDLR):​c.1845+1291C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 151,988 control chromosomes in the GnomAD database, including 11,887 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 0.38 (11887 hom., cov: 31)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.932
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1845+1291C>A		intron_variant	Intron 12 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1845+1291C>A		intron_variant	Intron 12 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57155 AN: 151870 Hom.: 11889 Cov.: 31

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.394

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.376 AC: 57179 AN: 151988 Hom.: 11887 Cov.: 31 AF XY: 0.380 AC XY: 28251 AN XY: 74290

African (AFR) AF: 0.204 AC: 8456 AN: 41478

American (AMR) AF: 0.506 AC: 7713 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1452 AN: 3464

East Asian (EAS) AF: 0.216 AC: 1112 AN: 5148

South Asian (SAS) AF: 0.430 AC: 2077 AN: 4826

European-Finnish (FIN) AF: 0.497 AC: 5249 AN: 10566

Middle Eastern (MID) AF: 0.421 AC: 123 AN: 292

European-Non Finnish (NFE) AF: 0.439 AC: 29853 AN: 67960

Other (OTH) AF: 0.392 AC: 826 AN: 2108

Alfa AF: 0.417 Hom.: 52490

Bravo AF: 0.368

Asia WGS AF: 0.337 AC: 1171 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.99
DANN	Benign	0.73
PhyloP100		-0.93
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: rs2738450; hg19: chr19-11228965;