12-52487848-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005554.4(KRT6A):c.1567G>A(p.Val523Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000764 in 1,613,996 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V523F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: KRT6A NM_005554.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.31

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057082474).
• BP6: Variant 12-52487848-C-T is Benign according to our data. Variant chr12-52487848-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 773545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-52487848-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00142 (216/152322) while in subpopulation AFR AF= 0.00402 (167/41560). AF 95% confidence interval is 0.00352. There are 1 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 216 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT6A	NM_005554.4	c.1567G>A	p.Val523Ile	missense_variant	9/9	ENST00000330722.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT6A	ENST00000330722.7	c.1567G>A	p.Val523Ile	missense_variant	9/9	1	NM_005554.4	P1

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000736 AC: 185 AN: 251250 Hom.: 1 AF XY: 0.000729 AC XY: 99 AN XY: 135810

Gnomad AFR exome AF: 0.00389

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000696 AC: 1017 AN: 1461674 Hom.: 1 Cov.: 35 AF XY: 0.000693 AC XY: 504 AN XY: 727140

Gnomad4 AFR exome AF: 0.00451

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000575

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74478

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000763 Hom.: 4

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000700 AC: 85

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KRT6A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 27, 2023

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

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	12
Dann	Benign	0.72
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.093	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.093
Sift	Benign	0.40	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.078
MVP		0.32
MPC		0.23
ClinPred		0.0011	T
GERP RS		-1.0
Varity_R		0.026
gMVP		0.21

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

Other links and lift over

dbSNP: rs62617088; hg19: chr12-52881632; COSMIC: COSV58107450; COSMIC: COSV58107450;