rs781321238
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_006846.4(SPINK5):βc.2211_2213delβ(p.Asn738del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000143 in 1,614,022 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000033 ( 0 hom., cov: 33)
Exomes π: 0.000012 ( 1 hom. )
Consequence
SPINK5
NM_006846.4 inframe_deletion
NM_006846.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.04
Genes affected
SPINK5 (HGNC:15464): (serine peptidase inhibitor Kazal type 5) This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. These proteins may play a role in skin and hair morphogenesis, as well as anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in this gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. This gene is present in a gene cluster on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_006846.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPINK5 | NM_006846.4 | c.2211_2213del | p.Asn738del | inframe_deletion | 23/33 | ENST00000256084.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPINK5 | ENST00000256084.8 | c.2211_2213del | p.Asn738del | inframe_deletion | 23/33 | 1 | NM_006846.4 | P2 | |
FBXO38-DT | ENST00000667608.1 | n.1257-24791_1257-24789del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152166Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249530Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135390
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461856Hom.: 1 AF XY: 0.0000124 AC XY: 9AN XY: 727230
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Netherton syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | This variant, c.2211_2213del, results in the deletion of 1 amino acid(s) of the SPINK5 protein (p.Asn738del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs781321238, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SPINK5-related conditions. ClinVar contains an entry for this variant (Variation ID: 451079). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2017 | The c.2211_2213delCAA variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The variant results in the in-frame deletion of the Asparagine at codon 738, a residue which is not conserved. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at