12-52286473-C-T

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

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.06
Variant links:
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]

Genome browser will be placed here

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
KRT81NM_002281.4 linkc.1300G>A p.Gly434Arg missense_variant Exon 9 of 9 ENST00000327741.9 NP_002272.2 Q14533
KRT86NM_001320198.2 linkc.-5+10527C>T intron_variant Intron 2 of 10 ENST00000423955.7 NP_001307127.1 O43790A8K872
KRT86XM_005268866.5 linkc.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
KRT81ENST00000327741.9 linkc.1300G>A p.Gly434Arg missense_variant Exon 9 of 9 1 NM_002281.4 ENSP00000369349.4 Q14533
KRT86ENST00000423955.7 linkc.-5+10527C>T intron_variant Intron 2 of 10 2 NM_001320198.2 ENSP00000444533.1 O43790
KRT86ENST00000553310.6 linkc.-4-15440C>T intron_variant Intron 1 of 2 4 ENSP00000452237.3 U3KPR1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152222
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000196
AC:
3
AN:
152950
Hom.:
0
AF XY:
0.0000368
AC XY:
3
AN XY:
81432
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000646
Gnomad NFE exome
AF:
0.0000351
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000207
AC:
29
AN:
1400088
Hom.:
0
Cov.:
33
AF XY:
0.0000203
AC XY:
14
AN XY:
690718
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000408
Gnomad4 NFE exome
AF:
0.0000213
Gnomad4 OTH exome
AF:
0.0000689
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000189
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

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

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
T;.
Eigen
Benign
0.10
Eigen_PC
Benign
0.079
FATHMM_MKL
Benign
0.17
N
LIST_S2
Uncertain
0.86
D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.41
T;T
MetaSVM
Uncertain
0.17
D
MutationAssessor
Uncertain
2.5
M;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-5.2
D;.
REVEL
Uncertain
0.56
Sift
Uncertain
0.023
D;.
Sift4G
Pathogenic
0.0010
D;D
Polyphen
0.75
P;.
Vest4
0.40
MutPred
0.42
Gain of catalytic residue at S431 (P = 0);Gain of catalytic residue at S431 (P = 0);
MVP
0.75
MPC
0.56
ClinPred
0.94
D
GERP RS
4.8
Varity_R
0.44
gMVP
0.089

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs772939014; hg19: chr12-52680257; API