rs2116897

Positions:

• chr19-11131201-G-A
• chr19-11131201-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):​c.2548-80G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,445,712 control chromosomes in the GnomAD database, including 43,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4151 hom., cov: 32)
  • Exomes 𝑓: 0.24 (39513 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.315

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-11131201-G-A is Benign according to our data. Variant chr19-11131201-G-A is described in ClinVar as [Benign]. Clinvar id is 265908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11131201-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2548-80G>A		intron_variant		ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2548-80G>A		intron_variant		1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34580 AN: 152012 Hom.: 4144 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.226

GnomAD4 exome AF: 0.243 AC: 314286 AN: 1293582 Hom.: 39513 AF XY: 0.241 AC XY: 156885 AN XY: 651854

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.261

Gnomad4 ASJ exome AF: 0.216

Gnomad4 EAS exome AF: 0.398

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.227 AC: 34602 AN: 152130 Hom.: 4151 Cov.: 32 AF XY: 0.226 AC XY: 16797 AN XY: 74380

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.239

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.225

Alfa AF: 0.238 Hom.: 699

Bravo AF: 0.230

Asia WGS AF: 0.296 AC: 1028 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	9 Hmz + 32 Htz / 95 non-FH individuals -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.5
DANN	Benign	0.69

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: rs2116897; hg19: chr19-11241877;