chr12-52286388-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002281.4(KRT81):c.1385C>T(p.Ala462Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,555,306 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A462E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.022 ( 120 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 102 hom. )

Consequence

KRT81
NM_002281.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.415

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017445982).

BP6

Variant 12-52286388-G-A is Benign according to our data. Variant chr12-52286388-G-A is described in ClinVar as Benign. ClinVar VariationId is 1264106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

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.1385C>T	p.Ala462Val	missense	Exon 9 of 9	NP_002272.2	Q14533
	KRT86	NM_001320198.2	MANE Select	c.-5+10442G>A		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.1385C>T	p.Ala462Val	missense	Exon 9 of 9	ENSP00000369349.4	Q14533
KRT86	ENST00000423955.7	TSL:2 MANE Select	c.-5+10442G>A		intron	N/A	ENSP00000444533.1	O43790
KRT86	ENST00000958042.1		c.-5+7704G>A		intron	N/A	ENSP00000628101.1

Frequencies

GnomAD3 genomes

AF:

0.0217

AC:

3298

AN:

152176

Hom.:

118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0745

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00923

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.00521

AC:

824

AN:

158094

AF XY:

0.00369

show subpopulations

Gnomad AFR exome

AF:

0.0751

Gnomad AMR exome

AF:

0.00358

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000429

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00229

AC:

3212

AN:

1403012

Hom.:

102

Cov.:

AF XY:

0.00197

AC XY:

1361

AN XY:

692386

show subpopulations

African (AFR)

AF:

0.0767

AC:

2443

AN:

31856

American (AMR)

AF:

0.00478

AC:

173

AN:

36178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25194

East Asian (EAS)

AF:

0.0000276

AC:

AN:

36218

South Asian (SAS)

AF:

0.000957

AC:

AN:

79444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49230

Middle Eastern (MID)

AF:

0.00197

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

0.000189

AC:

204

AN:

1081178

Other (OTH)

AF:

0.00523

AC:

304

AN:

58140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

215

430

645

860

1075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.0217

AC:

3310

AN:

152294

Hom.:

120

Cov.:

AF XY:

0.0210

AC XY:

1567

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0746

AC:

3101

AN:

41564

American (AMR)

AF:

0.00922

AC:

141

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68016

Other (OTH)

AF:

0.0180

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

161

322

483

644

805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00605

Hom.:

Bravo

AF:

0.0243

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00466

AC:

521

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.024

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.030

PhyloP100

-0.41

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.45

REVEL

Benign

0.20

Sift

Benign

0.60

Sift4G

Benign

0.68

Polyphen

0.0040

Vest4

0.13

MVP

0.31

MPC

0.37

ClinPred

0.0027

GERP RS

2.3

Varity_R

0.026

gMVP

0.056

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over