chr12-52286265-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002281.4(KRT81):c.1508G>A(p.Arg503Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,554,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

KRT81
NM_002281.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.373

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05891472).

BS2

High AC in GnomAd4 at 23 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.1508G>A	p.Arg503Gln	missense	Exon 9 of 9	NP_002272.2	Q14533
	KRT86	NM_001320198.2	MANE Select	c.-5+10319C>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.1508G>A	p.Arg503Gln	missense	Exon 9 of 9	ENSP00000369349.4	Q14533
KRT86	ENST00000423955.7	TSL:2 MANE Select	c.-5+10319C>T		intron	N/A	ENSP00000444533.1	O43790
KRT86	ENST00000958042.1		c.-5+7581C>T		intron	N/A	ENSP00000628101.1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000207

AC:

AN:

154228

AF XY:

0.000172

show subpopulations

Gnomad AFR exome

AF:

0.000113

Gnomad AMR exome

AF:

0.000281

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000156

Gnomad OTH exome

AF:

0.000690

GnomAD4 exome

AF:

0.000190

AC:

267

AN:

1401718

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

111

AN XY:

691618

show subpopulations

African (AFR)

AF:

0.0000314

AC:

AN:

31890

American (AMR)

AF:

0.000250

AC:

AN:

36040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.000358

AC:

AN:

36272

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5402

European-Non Finnish (NFE)

AF:

0.000213

AC:

230

AN:

1080414

Other (OTH)

AF:

0.000224

AC:

AN:

58066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000151

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41560

American (AMR)

AF:

0.000131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68012

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000272

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000464

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000830

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.4

PhyloP100

0.37

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.76

REVEL

Benign

0.24

Sift

Benign

0.055

Sift4G

Benign

0.069

Polyphen

0.99

Vest4

0.20

MVP

0.69

MPC

0.43

ClinPred

0.077

GERP RS

4.4

Varity_R

0.075

gMVP

0.044

Mutation Taster

=97/3

polymorphism

(source)

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

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