16-47596425-T-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000293.3(PHKB):c.1257T>A(p.Tyr419Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,612,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y419Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000293.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHKB | NM_000293.3 | c.1257T>A | p.Tyr419Ter | stop_gained | 13/31 | ENST00000323584.10 | |
PHKB | NM_001363837.1 | c.1257T>A | p.Tyr419Ter | stop_gained | 13/31 | ||
PHKB | NM_001031835.3 | c.1236T>A | p.Tyr412Ter | stop_gained | 14/32 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHKB | ENST00000323584.10 | c.1257T>A | p.Tyr419Ter | stop_gained | 13/31 | 1 | NM_000293.3 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251360Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135860
GnomAD4 exome AF: 0.000114 AC: 167AN: 1459880Hom.: 0 Cov.: 29 AF XY: 0.000100 AC XY: 73AN XY: 726440
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74336
ClinVar
Submissions by phenotype
Glycogen storage disease IXb Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change creates a premature translational stop signal (p.Tyr419*) in the PHKB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PHKB are known to be pathogenic (PMID: 9215682, 9326319). This variant is present in population databases (rs121918021, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 9215682). This variant is also known as Y418ter. ClinVar contains an entry for this variant (Variation ID: 13620). For these reasons, this variant has been classified as Pathogenic. - |
Glycogen phosphorylase kinase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 08, 2024 | Variant summary: PHKB c.1257T>A (p.Tyr419X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6e-05 in 251360 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PHKB causing Glycogen Phosphorylase Kinase Deficiency (6e-05 vs 0.0011), allowing no conclusion about variant significance. c.1257T>A has been reported in the literature in at least one compound heterozygous individual affected with Glycogen Phosphorylase Kinase Deficiency (e.g. Burwinkel_1997). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 9215682). ClinVar contains an entry for this variant (Variation ID: 13620). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at