rs759890511
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_006904.7(PRKDC):c.1862C>T(p.Ser621Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000196 in 1,581,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S621P) has been classified as Uncertain significance.
Frequency
Consequence
NM_006904.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKDC | NM_006904.7 | c.1862C>T | p.Ser621Leu | missense_variant | 17/86 | ENST00000314191.7 | |
PRKDC | NM_001081640.2 | c.1862C>T | p.Ser621Leu | missense_variant | 17/85 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKDC | ENST00000314191.7 | c.1862C>T | p.Ser621Leu | missense_variant | 17/86 | 1 | NM_006904.7 | P1 | |
PRKDC | ENST00000338368.7 | c.1862C>T | p.Ser621Leu | missense_variant | 17/85 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152128Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000182 AC: 26AN: 1429792Hom.: 0 Cov.: 30 AF XY: 0.0000198 AC XY: 14AN XY: 707972
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74318
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2023 | The p.S621L variant (also known as c.1862C>T), located in coding exon 17 of the PRKDC gene, results from a C to T substitution at nucleotide position 1862. The serine at codon 621 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 08, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Severe combined immunodeficiency due to DNA-PKcs deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 621 of the PRKDC protein (p.Ser621Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PRKDC-related conditions. ClinVar contains an entry for this variant (Variation ID: 541987). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at