rs2738459

Variant names:

• chr19-11127797-A-C
• rs2738459
• NM_000527.5:c.2312-211A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-11127797-A-C
• chr19-11127797-A-G
• chr19-11127797-A-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.2312-211A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 617,056 control chromosomes in the GnomAD database, including 80,131 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 0.53 (22173 hom., cov: 30)
  • Exomes 𝑓: 0.49 (57958 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.29
• Publications: 31 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 = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2312-211A>C		intron_variant	Intron 15 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2312-211A>C		intron_variant	Intron 15 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80232 AN: 151528 Hom.: 22132 Cov.: 30

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.525

GnomAD4 exome AF: 0.491 AC: 228389 AN: 465410 Hom.: 57958 AF XY: 0.489 AC XY: 121413 AN XY: 248472

African (AFR) AF: 0.682 AC: 8815 AN: 12916

American (AMR) AF: 0.432 AC: 10583 AN: 24500

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 6965 AN: 15106

East Asian (EAS) AF: 0.747 AC: 22452 AN: 30066

South Asian (SAS) AF: 0.480 AC: 24452 AN: 50966

European-Finnish (FIN) AF: 0.445 AC: 12872 AN: 28936

Middle Eastern (MID) AF: 0.425 AC: 1255 AN: 2952

European-Non Finnish (NFE) AF: 0.468 AC: 128059 AN: 273576

Other (OTH) AF: 0.490 AC: 12936 AN: 26392

GnomAD4 genome AF: 0.530 AC: 80332 AN: 151646 Hom.: 22173 Cov.: 30 AF XY: 0.527 AC XY: 39010 AN XY: 74070

African (AFR) AF: 0.678 AC: 28048 AN: 41390

American (AMR) AF: 0.431 AC: 6556 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1645 AN: 3464

East Asian (EAS) AF: 0.723 AC: 3647 AN: 5042

South Asian (SAS) AF: 0.492 AC: 2367 AN: 4810

European-Finnish (FIN) AF: 0.411 AC: 4323 AN: 10524

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31903 AN: 67894

Other (OTH) AF: 0.527 AC: 1109 AN: 2106

Alfa AF: 0.492 Hom.: 47711

Bravo AF: 0.540

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.17
DANN	Benign	0.31
PhyloP100		-2.3
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: rs2738459; hg19: chr19-11238473;