12-52447395-T-C

Position:

• chr12-52447395-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000252252.4(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 ENST00000252252.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.477

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]

ACMG classification

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/exons	MANE	Protein	UniProt
KRT6B	NM_005555.4	c.1490A>G	p.Tyr497Cys	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	c.1490A>G	p.Tyr497Cys	missense_variant	9/9	1	NM_005555.4	ENSP00000252252	P1

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5937 AN: 152100 Hom.: 144 Cov.: 33

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

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.: 31 AF XY: 0.0503 AC XY: 36588 AN XY: 727142

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.: 33 AF XY: 0.0390 AC XY: 2906 AN XY: 74426

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.: 97

Bravo AF: 0.0347

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0519 AC: 200

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.0534 AC: 459

ExAC AF: 0.0415 AC: 5032

Asia WGS AF: 0.0250 AC: 88 AN: 3478

EpiCase AF: 0.0531

EpiControl AF: 0.0492

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

KRT6B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

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	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.45
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.88	D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.20
Sift	Benign	0.17	T
Sift4G	Benign	0.15	T
Polyphen		0.069	B
Vest4		0.043
MPC		0.22
ClinPred		0.020	T
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

Other links and lift over

dbSNP: rs61746354; hg19: chr12-52841179;