17-40819077-G-GAGCTTCCGCCGCCGGAGCTT
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1
The NM_000421.5(KRT10):c.1457_1458insAAGCTCCGGCGGCGGAAGCT(p.His487SerfsTer139) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000678 in 145,958 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00068 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000051 ( 1 hom. )
Failed GnomAD Quality Control
Consequence
KRT10
NM_000421.5 frameshift
NM_000421.5 frameshift
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 2.66
Publications
1 publications found
Genes affected
KRT10 (HGNC:6413): (keratin 10) This gene encodes a member of the type I (acidic) cytokeratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. Mutations in this gene are associated with epidermolytic hyperkeratosis. This gene is located within a cluster of keratin family members on chromosome 17q21. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000421.5. 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 |
|---|---|---|---|---|---|---|---|---|---|
| KRT10 | NM_000421.5 | MANE Select | c.1457_1458insAAGCTCCGGCGGCGGAAGCT | p.His487SerfsTer139 | frameshift | Exon 7 of 8 | NP_000412.4 | ||
| KRT10 | NM_001379366.1 | c.1457_1458insAAGCTCCGGCGGCGGAAGCT | p.His487SerfsTer117 | frameshift | Exon 7 of 8 | NP_001366295.1 | A0A1B0GVI3 | ||
| KRT10-AS1 | NR_160886.1 | n.-108_-107insAGCTTCCGCCGCCGGAGCTT | upstream_gene | N/A |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KRT10 | ENST00000269576.6 | TSL:1 MANE Select | c.1457_1458insAAGCTCCGGCGGCGGAAGCT | p.His487SerfsTer139 | frameshift | Exon 7 of 8 | ENSP00000269576.5 | P13645 | |
| KRT10 | ENST00000635956.2 | TSL:2 | c.1457_1458insAAGCTCCGGCGGCGGAAGCT | p.His487SerfsTer117 | frameshift | Exon 7 of 8 | ENSP00000490524.2 | A0A1B0GVI3 | |
| KRT10-AS1 | ENST00000436612.7 | TSL:2 | n.7_8insAGCTTCCGCCGCCGGAGCTT | non_coding_transcript_exon | Exon 1 of 3 |
Frequencies
GnomAD3 genomes 0.000686 AC: 100AN: 145860Hom.: 0 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
100
AN:
145860
Hom.:
Cov.:
31
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
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GnomAD2 exomes AF: 0.0000705 AC: 5AN: 70924 AF XY: 0.0000721 show subpopulations
GnomAD2 exomes
AF:
AC:
5
AN:
70924
AF XY:
Gnomad AFR exome
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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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000509 AC: 64AN: 1258140Hom.: 1 Cov.: 34 AF XY: 0.0000581 AC XY: 36AN XY: 619688 show subpopulations
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
64
AN:
1258140
Hom.:
Cov.:
34
AF XY:
AC XY:
36
AN XY:
619688
show subpopulations
African (AFR)
AF:
AC:
52
AN:
25260
American (AMR)
AF:
AC:
0
AN:
23146
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
22012
East Asian (EAS)
AF:
AC:
0
AN:
26944
South Asian (SAS)
AF:
AC:
3
AN:
66878
European-Finnish (FIN)
AF:
AC:
0
AN:
30820
Middle Eastern (MID)
AF:
AC:
0
AN:
3974
European-Non Finnish (NFE)
AF:
AC:
4
AN:
1007452
Other (OTH)
AF:
AC:
5
AN:
51654
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.443
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
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>80
Age
GnomAD4 genome 0.000678 AC: 99AN: 145958Hom.: 0 Cov.: 31 AF XY: 0.000702 AC XY: 50AN XY: 71222 show subpopulations
GnomAD4 genome
AF:
AC:
99
AN:
145958
Hom.:
Cov.:
31
AF XY:
AC XY:
50
AN XY:
71222
show subpopulations
African (AFR)
AF:
AC:
93
AN:
39292
American (AMR)
AF:
AC:
3
AN:
14826
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3388
East Asian (EAS)
AF:
AC:
0
AN:
4868
South Asian (SAS)
AF:
AC:
0
AN:
4508
European-Finnish (FIN)
AF:
AC:
0
AN:
9932
Middle Eastern (MID)
AF:
AC:
0
AN:
276
European-Non Finnish (NFE)
AF:
AC:
1
AN:
66000
Other (OTH)
AF:
AC:
2
AN:
2000
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
5
10
15
20
25
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Genome Het
Variant carriers
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2
4
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8
10
<30
30-35
35-40
40-45
45-50
50-55
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>80
Age
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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