12-52286461-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002281.4(KRT81):c.1312G>A(p.Gly438Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,552,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

KRT81
NM_002281.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 1.98

Publications

0 publications found

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]

KRT81 links:

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):

monilethrix
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
monilethrix-1
Inheritance: AD Classification: MODERATE Submitted by: G2P

KRT86 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07796782).

BS2

High AC in GnomAd4 at 32 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002281.4. 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
	KRT81	NM_002281.4	MANE Select	c.1312G>A	p.Gly438Arg	missense	Exon 9 of 9	NP_002272.2	Q14533
	KRT86	NM_001320198.2	MANE Select	c.-5+10515C>T		intron	N/A	NP_001307127.1	O43790

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT81	ENST00000327741.9	TSL:1 MANE Select	c.1312G>A	p.Gly438Arg	missense	Exon 9 of 9	ENSP00000369349.4	Q14533
KRT86	ENST00000423955.7	TSL:2 MANE Select	c.-5+10515C>T		intron	N/A	ENSP00000444533.1	O43790
KRT86	ENST00000958042.1		c.-5+7777C>T		intron	N/A	ENSP00000628101.1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000371

AC:

AN:

153596

AF XY:

0.000343

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000160

Gnomad ASJ exome

AF:

0.00379

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000646

Gnomad NFE exome

AF:

0.0000698

Gnomad OTH exome

AF:

0.000455

GnomAD4 exome

AF:

0.000197

AC:

276

AN:

1400294

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

140

AN XY:

690850

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31656

American (AMR)

AF:

0.000111

AC:

AN:

36008

Ashkenazi Jewish (ASJ)

AF:

0.00488

AC:

123

AN:

25194

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35886

South Asian (SAS)

AF:

0.000555

AC:

AN:

79324

European-Finnish (FIN)

AF:

0.0000612

AC:

AN:

49026

Middle Eastern (MID)

AF:

0.000188

AC:

AN:

5320

European-Non Finnish (NFE)

AF:

0.0000639

AC:

AN:

1079838

Other (OTH)

AF:

0.000517

AC:

AN:

58042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000210

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41552

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000491

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000238

AC:

ExAC

AF:

0.000203

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

KRT81-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.0015

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.078

MetaSVM

Uncertain

0.55

MutationAssessor

Uncertain

2.5

PhyloP100

2.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.63

MutPred

0.41

Gain of catalytic residue at V436 (P = 0)

MVP

0.78

MPC

1.2

ClinPred

0.20

GERP RS

4.8

Varity_R

0.30

gMVP

0.16

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over