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

• 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

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 19-11127797-A-C is Benign according to our data. Variant chr19-11127797-A-C is described in Lovd as [Benign].
• 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

Gnomad4 AFR exome AF: 0.682

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.461

Gnomad4 EAS exome AF: 0.747

Gnomad4 SAS exome AF: 0.480

Gnomad4 FIN exome AF: 0.445

Gnomad4 NFE exome AF: 0.468

Gnomad4 OTH exome AF: 0.490

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

Gnomad4 AFR AF: 0.678

Gnomad4 AMR AF: 0.431

Gnomad4 ASJ AF: 0.475

Gnomad4 EAS AF: 0.723

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.470

Gnomad4 OTH AF: 0.527

Alfa AF: 0.475 Hom.: 28661

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

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: rs2738459; hg19: chr19-11238473;