rs2116897

Variant names:

• chr19-11131201-G-A
• rs2116897
• NM_000527.5:c.2548-80G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.315
• Publications: 11 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 -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 VariationId is 265908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2548-80G>A		intron_variant	Intron 17 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2548-80G>A		intron_variant	Intron 17 of 17	1	NM_000527.5	ENSP00000454071.1

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

African (AFR) AF: 0.163 AC: 4866 AN: 29846

American (AMR) AF: 0.261 AC: 11600 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5401 AN: 25052

East Asian (EAS) AF: 0.398 AC: 15511 AN: 38928

South Asian (SAS) AF: 0.179 AC: 14844 AN: 82888

European-Finnish (FIN) AF: 0.229 AC: 12181 AN: 53108

Middle Eastern (MID) AF: 0.174 AC: 949 AN: 5468

European-Non Finnish (NFE) AF: 0.246 AC: 235757 AN: 958886

Other (OTH) AF: 0.240 AC: 13177 AN: 54892

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

African (AFR) AF: 0.175 AC: 7276 AN: 41530

American (AMR) AF: 0.239 AC: 3651 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3472

East Asian (EAS) AF: 0.381 AC: 1967 AN: 5156

South Asian (SAS) AF: 0.193 AC: 930 AN: 4820

European-Finnish (FIN) AF: 0.217 AC: 2301 AN: 10594

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17044 AN: 67980

Other (OTH) AF: 0.225 AC: 475 AN: 2112

Alfa AF: 0.237 Hom.: 713

Bravo AF: 0.230

Asia WGS AF: 0.296 AC: 1028 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

9 Hmz + 32 Htz / 95 non-FH individuals -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.5
DANN	Benign	0.69
PhyloP100		0.32
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: rs2116897; hg19: chr19-11241877;