2-206766842-A-G
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001136193.2(FASTKD2):āc.149A>Gā(p.Lys50Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,609,052 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001136193.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FASTKD2 | NM_001136193.2 | c.149A>G | p.Lys50Arg | missense_variant | 2/12 | ENST00000402774.8 | NP_001129665.1 | |
FASTKD2 | NM_001136194.2 | c.149A>G | p.Lys50Arg | missense_variant | 2/12 | NP_001129666.1 | ||
FASTKD2 | NM_014929.4 | c.149A>G | p.Lys50Arg | missense_variant | 2/12 | NP_055744.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FASTKD2 | ENST00000402774.8 | c.149A>G | p.Lys50Arg | missense_variant | 2/12 | 1 | NM_001136193.2 | ENSP00000385990.3 |
Frequencies
GnomAD3 genomes AF: 0.00279 AC: 424AN: 152212Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.00263 AC: 652AN: 248234Hom.: 2 AF XY: 0.00259 AC XY: 348AN XY: 134154
GnomAD4 exome AF: 0.00411 AC: 5980AN: 1456722Hom.: 13 Cov.: 32 AF XY: 0.00400 AC XY: 2896AN XY: 723940
GnomAD4 genome AF: 0.00280 AC: 426AN: 152330Hom.: 2 Cov.: 33 AF XY: 0.00239 AC XY: 178AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 10, 2019 | This variant is associated with the following publications: (PMID: 25842392, 25842391, 25497598) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | FASTKD2: BP4, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 25, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The FASTKD2 p.Lys50Arg variant was identified in 1 of 70 proband chromosomes (frequency: 0.0143) from individuals with ataxia (Pyle_2014_PMID: 25497598). The variant was identified in dbSNP (ID: rs141447598) and ClinVar (classified as likely benign by GeneDx and Invitae, and as uncertain significance by Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics, CeGaT Praxis fuer Humangenetik Tuebingen, and Mayo Clinic). The variant was identified in control databases in 761 of 279634 chromosomes (2 homozygous) at a frequency of 0.002721 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 114 of 25062 chromosomes (freq: 0.004549), European (non-Finnish) in 535 of 128174 chromosomes (freq: 0.004174), Other in 23 of 7130 chromosomes (freq: 0.003226), Latino in 53 of 34698 chromosomes (freq: 0.001527), African in 17 of 24846 chromosomes (freq: 0.000684), South Asian in 15 of 29724 chromosomes (freq: 0.000505), Ashkenazi Jewish in 2 of 10180 chromosomes (freq: 0.000197), and East Asian in 2 of 19820 chromosomes (freq: 0.000101). The p.Lys50 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 25, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | - - |
Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
FASTKD2-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 11, 2021 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at