ENST00000359874.7:c.2812_2813delGT
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The ENST00000359874.7(SPINK5):c.2812_2813delGT(p.Val938CysfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000526 in 152,174 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000359874.7 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPINK5 | ENST00000359874.7 | c.2812_2813delGT | p.Val938CysfsTer7 | frameshift_variant | Exon 29 of 34 | 1 | ENSP00000352936.3 | |||
SPINK5 | ENST00000256084.8 | c.2740-127_2740-126delGT | intron_variant | Intron 28 of 32 | 1 | NM_006846.4 | ENSP00000256084.7 | |||
FBXO38-DT | ENST00000667608.1 | n.1257-31854_1257-31853delCA | intron_variant | Intron 3 of 4 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249426Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135364
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461866Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727232
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74352
ClinVar
Submissions by phenotype
Netherton syndrome Uncertain:1
The p.Val938CysfsX7 variant in SPINK5 has not been previously reported in individuals with disease and data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which would alter the protein’s amino acid sequence beginning at position 938 and lead to a premature termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. While complete loss of SPINK5 function has been previously described in many individuals with Netherton syndrome (Sprecher 2001), all previously described loss-of-function variants reside upstream of this variant. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant cannot be determined with certainty. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at