rs571668582
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The ENST00000289081.8(FANCC):āc.1634A>Gā(p.Lys545Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K545E) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000289081.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.1634A>G | p.Lys545Arg | missense_variant | 15/15 | ENST00000289081.8 | NP_000127.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.1634A>G | p.Lys545Arg | missense_variant | 15/15 | 1 | NM_000136.3 | ENSP00000289081 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251352Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135888
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29AN XY: 727198
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152276Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74470
ClinVar
Submissions by phenotype
Fanconi anemia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 10, 2022 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 545 of the FANCC protein (p.Lys545Arg). This variant is present in population databases (rs571668582, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 234672). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 04, 2020 | - - |
Fanconi anemia complementation group C Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 02, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The FANCC p.Lys545Arg variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or LOVD 3.0, databases. The variant was identified in dbSNP (ID: rs571668582) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was identified in control databases in 12 of 246178 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 11 of 30776 chromosomes (freq: 0.0004), European in 1 of 111666 chromosomes (freq: 0.000009), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Latino, and Other populations. The p.Lys545 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2015 | This variant is denoted FANCC c.1634A>G at the cDNA level, p.Lys545Arg (K545R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Lys545Arg was not observed at a significant allele frequency in 1000 Genomes. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. FANCC Lys545Arg occurs at a position that is not conserved and is located in a region responsible for cdc2 binding (Gordon and Buchwald). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether FANCC Lys545Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 04, 2021 | 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