5-148064089-C-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_006846.4(SPINK5):c.45C>A(p.Cys15Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 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 (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SPINK5
NM_006846.4 stop_gained
NM_006846.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 0.826
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 Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-148064089-C-A is Pathogenic according to our data. Variant chr5-148064089-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2060408.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPINK5 | NM_006846.4 | c.45C>A | p.Cys15Ter | stop_gained | 1/33 | ENST00000256084.8 | NP_006837.2 | |
SPINK5 | NM_001127698.2 | c.45C>A | p.Cys15Ter | stop_gained | 1/34 | NP_001121170.1 | ||
SPINK5 | NM_001127699.2 | c.45C>A | p.Cys15Ter | stop_gained | 1/28 | NP_001121171.1 | ||
SPINK5 | XM_047416662.1 | c.45C>A | p.Cys15Ter | stop_gained | 1/34 | XP_047272618.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPINK5 | ENST00000256084.8 | c.45C>A | p.Cys15Ter | stop_gained | 1/33 | 1 | NM_006846.4 | ENSP00000256084 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249496Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135358
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461848Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727226
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ichthyosis linearis circumflexa Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 12, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with SPINK5-related conditions. This variant is present in population databases (rs770450773, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Cys15*) 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). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A;A
Vest4
0.78, 0.72, 0.74
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at