rs761490126
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006846.4(SPINK5):c.817_818delAA(p.Asn273GlnfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,198 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
SPINK5
NM_006846.4 frameshift
NM_006846.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.27
Publications
0 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]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 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;
PP5
Variant 5-148095837-GAA-G is Pathogenic according to our data. Variant chr5-148095837-GAA-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 505094.Status of the report is criteria_provided_single_submitter, 1 stars.
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.817_818delAA | p.Asn273GlnfsTer2 | frameshift | Exon 10 of 33 | NP_006837.2 | Q9NQ38-1 | ||
| SPINK5 | c.817_818delAA | p.Asn273GlnfsTer2 | frameshift | Exon 10 of 34 | NP_001121170.1 | Q9NQ38-3 | |||
| SPINK5 | c.817_818delAA | p.Asn273GlnfsTer2 | frameshift | Exon 10 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.817_818delAA | p.Asn273GlnfsTer2 | frameshift | Exon 10 of 33 | ENSP00000256084.7 | Q9NQ38-1 | ||
| SPINK5 | TSL:1 | c.817_818delAA | p.Asn273GlnfsTer2 | frameshift | Exon 10 of 34 | ENSP00000352936.3 | Q9NQ38-3 | ||
| SPINK5 | TSL:1 | c.817_818delAA | p.Asn273GlnfsTer2 | frameshift | Exon 10 of 28 | ENSP00000381472.1 | Q9NQ38-2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000401 AC: 1AN: 249120 AF XY: 0.00000740 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
249120
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460198Hom.: 0 AF XY: 0.00000551 AC XY: 4AN XY: 726466 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
9
AN:
1460198
Hom.:
AF XY:
AC XY:
4
AN XY:
726466
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:
33382
American (AMR)
AF:
AC:
0
AN:
44574
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26060
East Asian (EAS)
AF:
AC:
0
AN:
39632
South Asian (SAS)
AF:
AC:
0
AN:
86224
European-Finnish (FIN)
AF:
AC:
0
AN:
53380
Middle Eastern (MID)
AF:
AC:
0
AN:
5742
European-Non Finnish (NFE)
AF:
AC:
9
AN:
1110924
Other (OTH)
AF:
AC:
0
AN:
60280
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000513610), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.381
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Likely pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Netherton syndrome (1)
Computational 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
You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.