12-52447395-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005555.4(KRT6B):c.1490A>G(p.Tyr497Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0486 in 1,613,936 control chromosomes in the GnomAD database, including 2,128 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 143 hom., cov: 33)

Exomes 𝑓: 0.050 ( 1985 hom. )

Consequence

KRT6B
NM_005555.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.477

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002239138).

BP6

Variant 12-52447395-T-C is Benign according to our data. Variant chr12-52447395-T-C is described in ClinVar as [Benign]. Clinvar id is 1603227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT6B	NM_005555.4 link	c.1490A>G	p.Tyr497Cys	missense_variant	Exon 9 of 9	ENST00000252252.4	NP_005546.2	P04259

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT6B	ENST00000252252.4 link	c.1490A>G	p.Tyr497Cys	missense_variant	Exon 9 of 9	1	NM_005555.4	ENSP00000252252.3		P04259

Frequencies

GnomAD3 genomes

AF:

0.0390

AC:

5937

AN:

152100

Hom.:

144

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.0321

Gnomad ASJ

AF:

0.0752

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.0527

Gnomad FIN

AF:

0.0670

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0530

Gnomad OTH

AF:

0.0359

GnomAD3 exomes

AF:

0.0429

AC:

10768

AN:

251184

Hom.:

297

AF XY:

0.0452

AC XY:

6139

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.00955

Gnomad AMR exome

AF:

0.0217

Gnomad ASJ exome

AF:

0.0755

Gnomad EAS exome

AF:

0.00141

Gnomad SAS exome

AF:

0.0557

Gnomad FIN exome

AF:

0.0602

Gnomad NFE exome

AF:

0.0510

Gnomad OTH exome

AF:

0.0449

GnomAD4 exome

AF:

0.0496

AC:

72462

AN:

1461718

Hom.:

1985

Cov.:

AF XY:

0.0503

AC XY:

36588

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00947

Gnomad4 AMR exome

AF:

0.0227

Gnomad4 ASJ exome

AF:

0.0742

Gnomad4 EAS exome

AF:

0.000781

Gnomad4 SAS exome

AF:

0.0559

Gnomad4 FIN exome

AF:

0.0594

Gnomad4 NFE exome

AF:

0.0522

Gnomad4 OTH exome

AF:

0.0486

GnomAD4 genome

AF:

0.0390

AC:

5930

AN:

152218

Hom.:

143

Cov.:

AF XY:

0.0390

AC XY:

2906

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0101

Gnomad4 AMR

AF:

0.0320

Gnomad4 ASJ

AF:

0.0752

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.0525

Gnomad4 FIN

AF:

0.0670

Gnomad4 NFE

AF:

0.0530

Gnomad4 OTH

AF:

0.0355

Alfa

AF:

0.0506

Hom.:

Bravo

AF:

0.0347

TwinsUK

AF:

0.0507

AC:

188

ALSPAC

AF:

0.0519

AC:

200

ESP6500AA

AF:

0.0129

AC:

ESP6500EA

AF:

0.0534

AC:

459

ExAC

AF:

0.0415

AC:

5032

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0531

EpiControl

AF:

0.0492

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

KRT6B-related disorder

Benign:1

Jan 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.45

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.3

REVEL

Benign

0.20

Sift

Benign

0.17

Sift4G

Benign

0.15

Polyphen

0.069

Vest4

0.043

MPC

0.22

ClinPred

0.020

GERP RS

2.0

Varity_R

0.27

gMVP

0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over