5-148120311-GAAA-GA
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2
The NM_006846.4(SPINK5):c.2467_2468delAA(p.Lys823GlufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,387,036 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000029 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SPINK5
NM_006846.4 frameshift
NM_006846.4 frameshift
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 1.94
Publications
17 publications found
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 was made for transcript
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_006846.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SPINK5 | MANE Select | c.2467_2468delAA | p.Lys823GlufsTer4 | frameshift | Exon 26 of 33 | NP_006837.2 | Q9NQ38-1 | ||
| SPINK5 | c.2467_2468delAA | p.Lys823GlufsTer4 | frameshift | Exon 26 of 34 | NP_001121170.1 | Q9NQ38-3 | |||
| SPINK5 | c.2467_2468delAA | p.Lys823GlufsTer4 | frameshift | Exon 26 of 28 | NP_001121171.1 | Q9NQ38-2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SPINK5 | TSL:1 MANE Select | c.2467_2468delAA | p.Lys823GlufsTer4 | frameshift | Exon 26 of 33 | ENSP00000256084.7 | Q9NQ38-1 | ||
| SPINK5 | TSL:1 | c.2467_2468delAA | p.Lys823GlufsTer4 | frameshift | Exon 26 of 34 | ENSP00000352936.3 | Q9NQ38-3 | ||
| SPINK5 | TSL:1 | c.2467_2468delAA | p.Lys823GlufsTer4 | frameshift | Exon 26 of 28 | ENSP00000381472.1 | Q9NQ38-2 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 146026Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
0
AN:
146026
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
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Gnomad ASJ
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Gnomad EAS
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Gnomad SAS
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
AF:
GnomAD2 exomes AF: 0.0000304 AC: 4AN: 131578 AF XY: 0.0000285 show subpopulations
GnomAD2 exomes
AF:
AC:
4
AN:
131578
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 0.00000288 AC: 4AN: 1387036Hom.: 0 AF XY: 0.00000145 AC XY: 1AN XY: 689508 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
4
AN:
1387036
Hom.:
AF XY:
AC XY:
1
AN XY:
689508
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
31322
American (AMR)
AF:
AC:
0
AN:
41102
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
24512
East Asian (EAS)
AF:
AC:
0
AN:
37218
South Asian (SAS)
AF:
AC:
0
AN:
81134
European-Finnish (FIN)
AF:
AC:
1
AN:
50786
Middle Eastern (MID)
AF:
AC:
0
AN:
5550
European-Non Finnish (NFE)
AF:
AC:
2
AN:
1058442
Other (OTH)
AF:
AC:
1
AN:
56970
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00 AC: 0AN: 146026Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 70798
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
146026
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
70798
African (AFR)
AF:
AC:
0
AN:
39804
American (AMR)
AF:
AC:
0
AN:
14604
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3402
East Asian (EAS)
AF:
AC:
0
AN:
5076
South Asian (SAS)
AF:
AC:
0
AN:
4594
European-Finnish (FIN)
AF:
AC:
0
AN:
9116
Middle Eastern (MID)
AF:
AC:
0
AN:
312
European-Non Finnish (NFE)
AF:
AC:
0
AN:
66244
Other (OTH)
AF:
AC:
0
AN:
1976
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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