12-52487848-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -14 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_single_submitter, 1 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	UniProt
KRT6A	NM_005554.4	c.1567G>T	p.Val523Phe	missense_variant	9/9	ENST00000330722.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT6A	ENST00000330722.7	c.1567G>T	p.Val523Phe	missense_variant	9/9	1	NM_005554.4	P1

Frequencies

GnomAD3 genomes AF: 0.0715 AC: 10887 AN: 152188 Hom.: 1006 Cov.: 33

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

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.: 35 AF XY: 0.0144 AC XY: 10454 AN XY: 727138

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.: 33 AF XY: 0.0718 AC XY: 5349 AN XY: 74464

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.: 4

Bravo AF: 0.0834

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.202 AC: 888

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.0355 AC: 4312

EpiCase AF: 0.00932

EpiControl AF: 0.00812

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	8.3
Dann	Benign	0.19
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.75	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.13
Sift	Benign	0.69	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.088
MPC		0.37
ClinPred		0.00067	T
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

Other links and lift over

dbSNP: rs62617088; hg19: chr12-52881632; COSMIC: COSV58106819; COSMIC: COSV58106819;