19-11100245-C-T
Variant summary
Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_000527.5(LDLR):c.90C>T(p.Asn30Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,613,462 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000527.5 synonymous
Scores
Clinical Significance
Conservation
Publications
- hypercholesterolemia, familial, 1Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
- homozygous familial hypercholesterolemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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LDLR | NM_000527.5 | c.90C>T | p.Asn30Asn | synonymous_variant | Exon 2 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00890 AC: 1354AN: 152090Hom.: 18 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00227 AC: 571AN: 251024 AF XY: 0.00171 show subpopulations
GnomAD4 exome AF: 0.000913 AC: 1334AN: 1461254Hom.: 19 Cov.: 31 AF XY: 0.000878 AC XY: 638AN XY: 726890 show subpopulations
GnomAD4 genome AF: 0.00893 AC: 1359AN: 152208Hom.: 18 Cov.: 33 AF XY: 0.00860 AC XY: 640AN XY: 74414 show subpopulations
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:1Benign:5
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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0/190 non-FH alleles -
Familial hypercholesterolemia Benign:4
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not specified Benign:2
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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not provided Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at