5-148120311-GAAA-GAA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006846.4(SPINK5):c.2468delA(p.Lys823ArgfsTer101) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,528,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006846.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000137 AC: 2AN: 146004Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00406 AC: 534AN: 131578Hom.: 0 AF XY: 0.00435 AC XY: 305AN XY: 70102
GnomAD4 exome AF: 0.000228 AC: 315AN: 1382014Hom.: 0 Cov.: 34 AF XY: 0.000252 AC XY: 173AN XY: 686958
GnomAD4 genome AF: 0.0000205 AC: 3AN: 146068Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1AN XY: 70858
ClinVar
Submissions by phenotype
Netherton syndrome Pathogenic:3
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NM_006846.3:c.2468delA in the SPINK5 gene has an allele frequency of 0.005 in South subpopulation in the gnomAD database. This variant has been reported previously in individuals with Netherton syndrome, including one compound heterozygote 1608-1G>A/2468delA and one homozygote (PMID: 11841556). The c.2468delA variant causes a frameshift starting with codon Lysine 823, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 101 of the new reading frame, denoted p.Lys823Argfs*101. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4. -
PM2_Supporting+PVS1+PM3_Strong+PP4 -
Ichthyosis linearis circumflexa Pathogenic:1
This sequence change creates a premature translational stop signal (p.Lys823Argfs*101) in the SPINK5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPINK5 are known to be pathogenic (PMID: 11511292, 11841556). 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 523932). This premature translational stop signal has been observed in individual(s) with Netherton syndrome (PMID: 11841556, 12923596, 26229701). -
not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 12923596, 27905021, 11841556, 26229701, 36262015, 31980526) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at