12-52447390-C-T

Position:

chr12-52447390-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000252252.4(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. 14/20 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
ENST00000252252.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.16

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=0.0018194914).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3744 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT6B	NM_005555.4 linkuse as main transcript	c.1495G>A	p.Gly499Ser	missense_variant	9/9	ENST00000252252.4	NP_005546.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT6B	ENST00000252252.4 linkuse as main transcript	c.1495G>A	p.Gly499Ser	missense_variant	9/9	1	NM_005555.4	ENSP00000252252	P1

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

GnomAD3 exomes

AF:

0.0259

AC:

6493

AN:

251172

Hom.:

121

AF XY:

0.0261

AC XY:

3538

AN XY:

135790

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 SAS exome

AF:

0.00853

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

Gnomad4 AFR exome

AF:

0.00502

Gnomad4 AMR exome

AF:

0.0217

Gnomad4 ASJ exome

AF:

0.0597

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00878

Gnomad4 FIN exome

AF:

0.0353

Gnomad4 NFE exome

AF:

0.0348

Gnomad4 OTH exome

AF:

0.0305

GnomAD4 genome

AF:

0.0246

AC:

3744

AN:

152292

Hom.:

Cov.:

AF XY:

0.0229

AC XY:

1706

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00570

Gnomad4 AMR

AF:

0.0220

Gnomad4 ASJ

AF:

0.0617

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00934

Gnomad4 FIN

AF:

0.0342

Gnomad4 NFE

AF:

0.0359

Gnomad4 OTH

AF:

0.0370

Alfa

AF:

0.0336

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

Significance: Benign

Submissions summary: Pathogenic:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pachyonychia congenita 4

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 06, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.023

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

MutationTaster

Benign

0.99

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

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