5-148120311-GAAA-GAAAA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006846.4(SPINK5):c.2468dupA(p.Lys824GlufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,361,340 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: 0.00 AC: 15AN: 146014Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.00133 AC: 175AN: 131578Hom.: 0 AF XY: 0.00120 AC XY: 84AN XY: 70102
GnomAD4 exome AF: 0.000220 AC: 299AN: 1361340Hom.: 0 Cov.: 34 AF XY: 0.000211 AC XY: 143AN XY: 676992
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000103 AC: 15AN: 146078Hom.: 0 Cov.: 32 AF XY: 0.0000847 AC XY: 6AN XY: 70866
ClinVar
Submissions by phenotype
Netherton syndrome Pathogenic:3
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.113%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000005268 / PMID: 10835624). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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Ichthyosis linearis circumflexa Pathogenic:2
Variant summary: SPINK5 c.2468dupA (p.Lys824GlufsX4) 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 0.0013 in 131578 control chromosomes (gnomAD). c.2468dupA (aka 2468insA) has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Netherton syndrome (e.g. Chavanas_2000, Bitoun_2002). These publications also reported dramatic reduction in the SPINK5 mRNA in keratinocytes derived from homozygous patients, suggestive of nonsense-mediated mRNA decay (Bitoun_2002). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10835624, 11841556). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Lys824Glufs*4) 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. This premature translational stop signal has been observed in individuals with Netherton syndrome (PMID: 10835624, 26031502). This variant is also known as 2468insA. ClinVar contains an entry for this variant (Variation ID: 5268). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
The c.2468dupA pathogenic variant in the SPINK5 gene has been reported previously in the homozygous state or as a single variant in patients with Netherton syndrome (Chavanas et al., 2000; Bitoun et al., 2002; Raghunath et al., 2004). It causes a frameshift starting with codon Lysine 824, changes this amino acid to a Glutamic acid residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Lys824GlufsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2468dupA variant is observed in 17/7814 (0.22%) alleles from individuals of African background, in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.2468dupA as a pathogenic variant. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at