12-52286473-C-T
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_002281.4(KRT81):c.1300G>A(p.Gly434Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,552,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
KRT81
NM_002281.4 missense
NM_002281.4 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 2.06
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.40857995).
BS2
High AC in GnomAdExome4 at 29 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KRT81 | NM_002281.4 | c.1300G>A | p.Gly434Arg | missense_variant | Exon 9 of 9 | ENST00000327741.9 | NP_002272.2 | |
KRT86 | NM_001320198.2 | c.-5+10527C>T | intron_variant | Intron 2 of 10 | ENST00000423955.7 | NP_001307127.1 | ||
KRT86 | XM_005268866.5 | c.129+10527C>T | 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.1300G>A | p.Gly434Arg | missense_variant | Exon 9 of 9 | 1 | NM_002281.4 | ENSP00000369349.4 | ||
KRT86 | ENST00000423955.7 | c.-5+10527C>T | intron_variant | Intron 2 of 10 | 2 | NM_001320198.2 | ENSP00000444533.1 | |||
KRT86 | ENST00000553310.6 | c.-4-15440C>T | intron_variant | Intron 1 of 2 | 4 | ENSP00000452237.3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000196 AC: 3AN: 152950Hom.: 0 AF XY: 0.0000368 AC XY: 3AN XY: 81432
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GnomAD4 exome AF: 0.0000207 AC: 29AN: 1400088Hom.: 0 Cov.: 33 AF XY: 0.0000203 AC XY: 14AN XY: 690718
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74376
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
MONILETHRIX 1 Uncertain:1
Sep 28, 2021
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research
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Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Pathogenic
D;D
Polyphen
P;.
Vest4
MutPred
Gain of catalytic residue at S431 (P = 0);Gain of catalytic residue at S431 (P = 0);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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