12-52286320-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002281.4(KRT81):​c.1453G>A​(p.Val485Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,554,588 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0041 ( 3 hom., cov: 33)
Exomes 𝑓: 0.00053 ( 7 hom. )

Consequence

KRT81
NM_002281.4 missense

Scores

18

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0250
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0057397485).
BP6
Variant 12-52286320-C-T is Benign according to our data. Variant chr12-52286320-C-T is described in ClinVar as [Benign]. Clinvar id is 1701200.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000528 (741/1402230) while in subpopulation AFR AF= 0.017 (541/31840). AF 95% confidence interval is 0.0158. There are 7 homozygotes in gnomad4_exome. There are 312 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 626 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRT81NM_002281.4 linkc.1453G>A p.Val485Met missense_variant Exon 9 of 9 ENST00000327741.9 NP_002272.2 Q14533
KRT86NM_001320198.2 linkc.-5+10374C>T intron_variant Intron 2 of 10 ENST00000423955.7 NP_001307127.1 O43790A8K872
KRT86XM_005268866.5 linkc.129+10374C>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.1453G>A p.Val485Met missense_variant Exon 9 of 9 1 NM_002281.4 ENSP00000369349.4 Q14533
KRT86ENST00000423955.7 linkc.-5+10374C>T intron_variant Intron 2 of 10 2 NM_001320198.2 ENSP00000444533.1 O43790
KRT86ENST00000553310.6 linkc.-4-15593C>T intron_variant Intron 1 of 2 4 ENSP00000452237.3 U3KPR1

Frequencies

GnomAD3 genomes
AF:
0.00411
AC:
625
AN:
152240
Hom.:
3
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0142
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00150
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00102
AC:
159
AN:
155904
Hom.:
2
AF XY:
0.000632
AC XY:
52
AN XY:
82264
show subpopulations
Gnomad AFR exome
AF:
0.0154
Gnomad AMR exome
AF:
0.000521
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000436
Gnomad FIN exome
AF:
0.0000643
Gnomad NFE exome
AF:
0.0000848
Gnomad OTH exome
AF:
0.000229
GnomAD4 exome
AF:
0.000528
AC:
741
AN:
1402230
Hom.:
7
Cov.:
33
AF XY:
0.000451
AC XY:
312
AN XY:
691884
show subpopulations
Gnomad4 AFR exome
AF:
0.0170
Gnomad4 AMR exome
AF:
0.000722
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000277
Gnomad4 SAS exome
AF:
0.0000630
Gnomad4 FIN exome
AF:
0.0000203
Gnomad4 NFE exome
AF:
0.0000824
Gnomad4 OTH exome
AF:
0.00112
GnomAD4 genome
AF:
0.00411
AC:
626
AN:
152358
Hom.:
3
Cov.:
33
AF XY:
0.00372
AC XY:
277
AN XY:
74512
show subpopulations
Gnomad4 AFR
AF:
0.0142
Gnomad4 AMR
AF:
0.00150
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000843
Hom.:
1
Bravo
AF:
0.00472
ESP6500AA
AF:
0.0130
AC:
56
ESP6500EA
AF:
0.000236
AC:
2
ExAC
AF:
0.000963
AC:
107
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Jul 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

KRT81: BP4, BS1, BS2; KRT86: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
14
DANN
Benign
0.95
DEOGEN2
Benign
0.024
T
Eigen
Benign
-0.12
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.39
T
MetaRNN
Benign
0.0057
T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
1.5
L
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.080
N
REVEL
Benign
0.22
Sift
Benign
0.079
T
Sift4G
Benign
0.22
T
Polyphen
1.0
D
Vest4
0.29
MVP
0.51
MPC
0.37
ClinPred
0.030
T
GERP RS
3.3
Varity_R
0.027
gMVP
0.050

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs115355093; hg19: chr12-52680104; COSMIC: COSV59809487; API