NM_002281.4:c.1204G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM5PP3BS2

The NM_002281.4(KRT81):c.1204G>C(p.Glu402Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,613,490 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E402K) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

KRT81
NM_002281.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.05

Publications

4 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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 -1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-52287145-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 7502.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.756

BS2

High AC in GnomAd4 at 89 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT81	NM_002281.4 link	c.1204G>C	p.Glu402Gln	missense_variant	Exon 7 of 9	ENST00000327741.9	NP_002272.2	Q14533
KRT86	NM_001320198.2 link	c.-5+11199C>G		intron_variant	Intron 2 of 10	ENST00000423955.7	NP_001307127.1	O43790A8K872
KRT86	XM_005268866.5 link	c.129+11199C>G		intron_variant	Intron 2 of 10		XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRT81	ENST00000327741.9 link	c.1204G>C	p.Glu402Gln	missense_variant	Exon 7 of 9	1	NM_002281.4	ENSP00000369349.4	Q14533
KRT86	ENST00000423955.7 link	c.-5+11199C>G		intron_variant	Intron 2 of 10	2	NM_001320198.2	ENSP00000444533.1	O43790
KRT86	ENST00000553310.6 link	c.-4-14768C>G		intron_variant	Intron 1 of 2	4		ENSP00000452237.3	U3KPR1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00113

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000486

AC:

122

AN:

251186

AF XY:

0.000479

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000968

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00105

AC:

1534

AN:

1461166

Hom.:

Cov.:

AF XY:

0.000985

AC XY:

716

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33458

American (AMR)

AF:

0.000201

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5212

European-Non Finnish (NFE)

AF:

0.00133

AC:

1480

AN:

1111982

Other (OTH)

AF:

0.000580

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

113

226

340

453

566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.000584

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41572

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

68034

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000916

Hom.:

Bravo

AF:

0.000646

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000486

AC:

EpiCase

AF:

0.000981

EpiControl

AF:

0.000830

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.8

H;.

PhyloP100

5.1

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.9

D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.96

MVP

0.96

MPC

1.2

ClinPred

0.29

GERP RS

5.3

Varity_R

0.85

gMVP

0.47

Mutation Taster

=7/93

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over