chr2-43832056-G-C
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_022436.3(ABCG5):āc.293C>Gā(p.Ala98Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,581,976 control chromosomes in the GnomAD database, including 13 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_022436.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00200 AC: 304AN: 152162Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00237 AC: 463AN: 194998Hom.: 1 AF XY: 0.00254 AC XY: 267AN XY: 105104
GnomAD4 exome AF: 0.00214 AC: 3061AN: 1429696Hom.: 12 Cov.: 33 AF XY: 0.00218 AC XY: 1542AN XY: 707604
GnomAD4 genome AF: 0.00200 AC: 304AN: 152280Hom.: 1 Cov.: 32 AF XY: 0.00208 AC XY: 155AN XY: 74458
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:1
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Variant summary: ABCG5 c.293C>G (p.Ala98Gly) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 194998 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCG5 causing Early Onset Coronary Artery Disease (0.0024 vs 0.005), allowing no conclusion about variant significance. c.293C>G has been reported in the literature in individuals affected with Congenital macrothrombocytopenia (Ali_2016), hypercholesterolemia (Corral_2018, Toton-Zuranska_2023), Hypoalphalipoproteinaemia (Dong_2022), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27291889, 30270055, 35460704, 36648309). ClinVar contains an entry for this variant (Variation ID: 289815). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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Sitosterolemia 1 Uncertain:1Benign:1
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided Benign:2
See Variant Classification Assertion Criteria. -
ABCG5: BS1, BS2 -
Hyperuricemic nephropathy, familial juvenile type 4 Uncertain:1
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ABCG5-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Sitosterolemia 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at