chr19-11128131-C-T

Variant names:

• chr19-11128131-C-T
• rs2738460
• NM_000527.5:c.2389+46C>T

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.2389+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,553,346 control chromosomes in the GnomAD database, including 47,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4112 hom., cov: 31)
  • Exomes 𝑓: 0.25 (43561 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.00
• Publications: 16 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=-0.85).
• BP6: Variant 19-11128131-C-T is Benign according to our data. Variant chr19-11128131-C-T is described in ClinVar as Benign. ClinVar VariationId is 265907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2389+46C>T		intron	N/A	NP_000518.1
	LDLR	NM_001195798.2		c.2389+46C>T		intron	N/A	NP_001182727.1
	LDLR	NM_001195799.2		c.2266+46C>T		intron	N/A	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2389+46C>T		intron	N/A	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2647+46C>T		intron	N/A	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2389+46C>T		intron	N/A	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34227 AN: 151926 Hom.: 4107 Cov.: 31

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.226

GnomAD2 exomes AF: 0.245 AC: 61232 AN: 250118 AF XY: 0.241

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.383

Gnomad FIN exome AF: 0.223

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.246 AC: 344863 AN: 1401302 Hom.: 43561 Cov.: 23 AF XY: 0.244 AC XY: 170809 AN XY: 700566

African (AFR) AF: 0.149 AC: 4818 AN: 32248

American (AMR) AF: 0.256 AC: 11412 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5538 AN: 25754

East Asian (EAS) AF: 0.400 AC: 15755 AN: 39420

South Asian (SAS) AF: 0.179 AC: 15221 AN: 85068

European-Finnish (FIN) AF: 0.233 AC: 12305 AN: 52854

Middle Eastern (MID) AF: 0.172 AC: 968 AN: 5634

European-Non Finnish (NFE) AF: 0.250 AC: 264692 AN: 1057272

Other (OTH) AF: 0.242 AC: 14154 AN: 58444

GnomAD4 genome AF: 0.225 AC: 34251 AN: 152044 Hom.: 4112 Cov.: 31 AF XY: 0.224 AC XY: 16618 AN XY: 74334

African (AFR) AF: 0.161 AC: 6672 AN: 41502

American (AMR) AF: 0.238 AC: 3620 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3470

East Asian (EAS) AF: 0.385 AC: 1973 AN: 5128

South Asian (SAS) AF: 0.192 AC: 924 AN: 4822

European-Finnish (FIN) AF: 0.220 AC: 2336 AN: 10600

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

European-Non Finnish (NFE) AF: 0.254 AC: 17292 AN: 67962

Other (OTH) AF: 0.225 AC: 476 AN: 2114

Alfa AF: 0.178 Hom.: 529

Bravo AF: 0.227

Asia WGS AF: 0.295 AC: 1023 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:4

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.052
DANN	Benign	0.54
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2738460; hg19: chr19-11238807; COSMIC: COSV52942258; COSMIC: COSV52942258;