chr8-47935842-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_006904.7(PRKDC):c.1337T>A(p.Phe446Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,978 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. F446L) has been classified as Likely benign.
Frequency
Consequence
NM_006904.7 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 | UniProt |
---|---|---|---|---|---|---|---|
PRKDC | NM_006904.7 | c.1337T>A | p.Phe446Tyr | missense_variant | 13/86 | ENST00000314191.7 | |
PRKDC | NM_001081640.2 | c.1337T>A | p.Phe446Tyr | missense_variant | 13/85 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKDC | ENST00000314191.7 | c.1337T>A | p.Phe446Tyr | missense_variant | 13/86 | 1 | NM_006904.7 | P1 | |
PRKDC | ENST00000338368.7 | c.1337T>A | p.Phe446Tyr | missense_variant | 13/85 | 1 | |||
PRKDC | ENST00000697591.1 | n.1378T>A | non_coding_transcript_exon_variant | 13/15 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000401 AC: 10AN: 249246Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135220
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461670Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727130
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74484
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 22, 2021 | The c.1337T>A (p.F446Y) alteration is located in exon 13 (coding exon 13) of the PRKDC gene. This alteration results from a T to A substitution at nucleotide position 1337, causing the phenylalanine (F) at amino acid position 446 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 08, 2024 | Variant summary: PRKDC c.1337T>A (p.Phe446Tyr) results in a conservative amino acid change located in the DNA-PKcs, N-terminal (IPR046804) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249246 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PRKDC causing Severe Combined Immunodeficiency (4e-05 vs 0.00035), allowing no conclusion about variant significance. c.1337T>A has been reported in the literature in individuals affected with systemic lupus erythematosus like syndrome (Li_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 37580814). ClinVar contains an entry for this variant (Variation ID: 475217). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Severe combined immunodeficiency due to DNA-PKcs deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 08, 2022 | This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 446 of the PRKDC protein (p.Phe446Tyr). This variant is present in population databases (rs534735519, gnomAD 0.05%). 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: 475217). 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