chr12-52288038-A-G
Variant names:
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7
The NM_002281.4(KRT81):c.846T>C(p.Tyr282Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
KRT81
NM_002281.4 synonymous
NM_002281.4 synonymous
Scores
2
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: -0.964
Publications
5 publications found
Genes affected
KRT81 (HGNC:6458): (keratin 81) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. All hair keratins are expressed in the hair follicle; this hair keratin, as well as KRTHB3 and KRTHB6, is found primarily in the hair cortex. Mutations in this gene and KRTHB6 have been observed in patients with a rare dominant hair disease, monilethrix. Some human genome assemblies (example T2T-CHM13) have a non-coding version of the gene due to the presence of a SNP that introduces a premature stop codon after codon 281. [provided by RefSeq, Jan 2024]
KRT86 (HGNC:6463): (keratin 86) This gene encodes a type II keratin protein, which heterodimerizes with type I keratins to form hair and nails. This gene is present in a cluster of related genes and pseudogenes on chromosome 12. Mutations in this gene have been observed in patients with the hair disease monilethrix. [provided by RefSeq, Feb 2016]
KRT86 Gene-Disease associations (from GenCC):
- monilethrixInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
- monilethrix-1Inheritance: AD Classification: MODERATE Submitted by: G2P
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ACMG classification
Classification was made for transcript
Our verdict: Likely_benign. The variant received -5 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP7
Synonymous conserved (PhyloP=-0.964 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| KRT81 | NM_002281.4 | c.846T>C | p.Tyr282Tyr | synonymous_variant | Exon 5 of 9 | ENST00000327741.9 | NP_002272.2 | |
| KRT86 | NM_001320198.2 | c.-5+12092A>G | intron_variant | Intron 2 of 10 | ENST00000423955.7 | NP_001307127.1 | ||
| KRT86 | XM_005268866.5 | c.129+12092A>G | intron_variant | Intron 2 of 10 | XP_005268923.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KRT81 | ENST00000327741.9 | c.846T>C | p.Tyr282Tyr | synonymous_variant | Exon 5 of 9 | 1 | NM_002281.4 | ENSP00000369349.4 | ||
| KRT86 | ENST00000423955.7 | c.-5+12092A>G | intron_variant | Intron 2 of 10 | 2 | NM_001320198.2 | ENSP00000444533.1 | |||
| KRT86 | ENST00000553310.6 | c.-4-13875A>G | intron_variant | Intron 1 of 2 | 4 | ENSP00000452237.3 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 33 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
152188
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD2 exomes AF: 0.00000795 AC: 2AN: 251476 AF XY: 0.00000736 show subpopulations
GnomAD2 exomes
AF:
AC:
2
AN:
251476
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
AF:
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461872Hom.: 0 Cov.: 85 AF XY: 0.0000165 AC XY: 12AN XY: 727228 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
24
AN:
1461872
Hom.:
Cov.:
85
AF XY:
AC XY:
12
AN XY:
727228
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:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
17
AN:
86244
European-Finnish (FIN)
AF:
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
6
AN:
1112008
Other (OTH)
AF:
AC:
1
AN:
60392
⚠️ 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: 0.335
Heterozygous variant carriers
0
1
3
4
6
7
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
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55-60
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>80
Age
GnomAD4 genome 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74332 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
2
AN:
152188
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74332
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
1
AN:
41448
American (AMR)
AF:
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5200
South Asian (SAS)
AF:
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68038
Other (OTH)
AF:
AC:
0
AN:
2090
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.350
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
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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