rs72646508
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_174936.4(PCSK9):c.757C>T(p.Leu253Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,613,232 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L253H) has been classified as Uncertain significance.
Frequency
Consequence
NM_174936.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000893 AC: 136AN: 152258Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.000193 AC: 48AN: 248974Hom.: 0 AF XY: 0.000141 AC XY: 19AN XY: 135104
GnomAD4 exome AF: 0.0000917 AC: 134AN: 1460856Hom.: 2 Cov.: 82 AF XY: 0.0000853 AC XY: 62AN XY: 726752
GnomAD4 genome AF: 0.000893 AC: 136AN: 152376Hom.: 0 Cov.: 35 AF XY: 0.000859 AC XY: 64AN XY: 74510
ClinVar
Submissions by phenotype
not provided Benign:3
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Variant summary: The PCSK9 c.757C>T (p.Leu253Phe) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 31/118852 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0030852 (31/10048). This frequency is about 33 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.0000938), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Moreover, the variant was reported to be associated with about a 30% reduction of LDL-C levels further supporting a non-disease causing impact. Taken together, this variant is classified as benign. -
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Hypercholesterolemia, autosomal dominant, 3 Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as 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. -
Familial hypercholesterolemia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at