Variant chr12-52487848-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_005554.4(KRT6A):c.1567G>T(p.Val523Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,613,990 control chromosomes in the GnomAD database, including 2,129 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V523I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.072 ( 1013 hom., cov: 33)

Exomes 𝑓: 0.015 ( 1116 hom. )

Consequence

KRT6A
NM_005554.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.31

Variant links:

Genes affected

KRT6A (HGNC:6443): (keratin 6A) 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. This KRT6 gene in particular encodes the most abundant isoform. Mutations in these genes have been associated with pachyonychia congenita. In addition, peptides from the C-terminal region of the protein have antimicrobial activity against bacterial pathogens. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Oct 2014]

KRT6A 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=0.0022658408).

BP6

Variant 12-52487848-C-A is Benign according to our data. Variant chr12-52487848-C-A is described in ClinVar as [Benign]. Clinvar id is 1601017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT6A	NM_005554.4 link	c.1567G>T	p.Val523Phe	missense_variant	9/9	ENST00000330722.7	NP_005545.1	P02538A0A0S2Z428

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT6A	ENST00000330722.7 link	c.1567G>T	p.Val523Phe	missense_variant	9/9	1	NM_005554.4	ENSP00000369317.3		P02538

Frequencies

GnomAD3 genomes

AF:

0.0715

AC:

10887

AN:

152188

Hom.:

1006

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0719

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.0486

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.00626

Gnomad OTH

AF:

0.0573

GnomAD3 exomes

AF:

0.0343

AC:

8623

AN:

251250

Hom.:

543

AF XY:

0.0284

AC XY:

3857

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.217

Gnomad AMR exome

AF:

0.0758

Gnomad ASJ exome

AF:

0.00992

Gnomad EAS exome

AF:

0.0482

Gnomad SAS exome

AF:

0.0182

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00676

Gnomad OTH exome

AF:

0.0264

GnomAD4 exome

AF:

0.0151

AC:

22025

AN:

1461684

Hom.:

1116

Cov.:

AF XY:

0.0144

AC XY:

10454

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.0777

Gnomad4 ASJ exome

AF:

0.00949

Gnomad4 EAS exome

AF:

0.0382

Gnomad4 SAS exome

AF:

0.0185

Gnomad4 FIN exome

AF:

0.000674

Gnomad4 NFE exome

AF:

0.00540

Gnomad4 OTH exome

AF:

0.0262

GnomAD4 genome

AF:

0.0718

AC:

10928

AN:

152306

Hom.:

1013

Cov.:

AF XY:

0.0718

AC XY:

5349

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.214

Gnomad4 AMR

AF:

0.0720

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.0485

Gnomad4 SAS

AF:

0.0207

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00626

Gnomad4 OTH

AF:

0.0558

Alfa

AF:

0.00690

Hom.:

Bravo

AF:

0.0834

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.202

AC:

888

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.0355

AC:

4312

EpiCase

AF:

0.00932

EpiControl

AF:

0.00812

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.3

DANN

Benign

0.19

DEOGEN2

Benign

0.14

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.75

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.83

REVEL

Benign

0.13

Sift

Benign

0.69

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.088

MPC

0.37

ClinPred

0.00067

GERP RS

-1.0

Varity_R

0.047

gMVP

0.38

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

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