NM_005555.4:c.1495G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005555.4(KRT6B):c.1495G>A(p.Gly499Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,614,014 control chromosomes in the GnomAD database, including 943 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 64 hom., cov: 33)

Exomes 𝑓: 0.032 ( 879 hom. )

Consequence

KRT6B
NM_005555.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:3

Conservation

PhyloP100: -1.16

Publications

11 publications found

Variant links:

Genes affected

KRT6B (HGNC:6444): (keratin 6B) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. As many as six of this type II cytokeratin (KRT6) have been identified; the multiplicity of the genes is attributed to successive gene duplication events. The genes are expressed with family members KRT16 and/or KRT17 in the filiform papillae of the tongue, the stratified epithelial lining of oral mucosa and esophagus, the outer root sheath of hair follicles, and the glandular epithelia. Mutations in these genes have been associated with pachyonychia congenita. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

KRT6B Gene-Disease associations (from GenCC):

pachyonychia congenita 4
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
pachyonychia congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRT6B 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=0.0018194914).

BP6

Variant 12-52447390-C-T is Benign according to our data. Variant chr12-52447390-C-T is described in ClinVar as Benign. ClinVar VariationId is 802862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0246 (3744/152292) while in subpopulation NFE AF = 0.0359 (2440/68026). AF 95% confidence interval is 0.0347. There are 64 homozygotes in GnomAd4. There are 1706 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3744 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005555.4. 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
	KRT6B	NM_005555.4	MANE Select	c.1495G>A	p.Gly499Ser	missense	Exon 9 of 9	NP_005546.2	P04259

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT6B	ENST00000252252.4	TSL:1 MANE Select	c.1495G>A	p.Gly499Ser	missense	Exon 9 of 9	ENSP00000252252.3	P04259

Frequencies

GnomAD3 genomes

AF:

0.0246

AC:

3748

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00572

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.0617

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00933

Gnomad FIN

AF:

0.0342

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0359

Gnomad OTH

AF:

0.0374

GnomAD2 exomes

AF:

0.0259

AC:

6493

AN:

251172

AF XY:

0.0261

show subpopulations

Gnomad AFR exome

AF:

0.00548

Gnomad AMR exome

AF:

0.0201

Gnomad ASJ exome

AF:

0.0567

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0329

Gnomad NFE exome

AF:

0.0350

Gnomad OTH exome

AF:

0.0307

GnomAD4 exome

AF:

0.0315

AC:

46089

AN:

1461722

Hom.:

879

Cov.:

AF XY:

0.0313

AC XY:

22777

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.00502

AC:

168

AN:

33472

American (AMR)

AF:

0.0217

AC:

970

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0597

AC:

1559

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00878

AC:

757

AN:

86252

European-Finnish (FIN)

AF:

0.0353

AC:

1887

AN:

53418

Middle Eastern (MID)

AF:

0.0392

AC:

226

AN:

5764

European-Non Finnish (NFE)

AF:

0.0348

AC:

38680

AN:

1111896

Other (OTH)

AF:

0.0305

AC:

1841

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

3367

6733

10100

13466

16833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1404

2808

4212

5616

7020

<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:

0.0246

AC:

3744

AN:

152292

Hom.:

Cov.:

AF XY:

0.0229

AC XY:

1706

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00570

AC:

237

AN:

41570

American (AMR)

AF:

0.0220

AC:

336

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0617

AC:

214

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00934

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0342

AC:

363

AN:

10610

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0359

AC:

2440

AN:

68026

Other (OTH)

AF:

0.0370

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

190

380

569

759

949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0305

Hom.:

Bravo

AF:

0.0235

TwinsUK

AF:

0.0280

AC:

104

ALSPAC

AF:

0.0343

AC:

132

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.0367

AC:

316

ExAC

AF:

0.0253

AC:

3076

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0346

EpiControl

AF:

0.0373

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Pachyonychia congenita 4 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.023

(source)

DANN

Benign

0.64

DEOGEN2

Uncertain

0.45

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0058

LIST_S2

Benign

0.10

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.84

MutationAssessor

Benign

-1.1

PhyloP100

-1.2

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.18

Sift

Benign

0.37

Sift4G

Benign

0.14

Polyphen

0.0020

Vest4

0.050

MPC

0.17

ClinPred

0.013

GERP RS

-3.3

Varity_R

0.065

gMVP

0.39

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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