12-52447318-C-A

Variant names:

• chr12-52447318-C-A
• rs146173634
• NM_005555.4:c.1567G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005555.4(KRT6B):​c.1567G>T​(p.Val523Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 33)
• Consequence: KRT6B NM_005555.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0130
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• pachyonychia congenita 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• pachyonychia congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06646365).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005555.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT6B	NM_005555.4	MANE Select	c.1567G>T	p.Val523Phe	missense	Exon 9 of 9	NP_005546.2	P04259

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT6B	ENST00000252252.4	TSL:1 MANE Select	c.1567G>T	p.Val523Phe	missense	Exon 9 of 9	ENSP00000252252.3	P04259

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	11
DANN	Benign	0.38
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.10	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.75	N
PhyloP100		0.013
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.17
Sift	Benign	0.71	T
Sift4G	Benign	0.70	T
Polyphen		0.028	B
Vest4		0.14
MutPred		0.36		Gain of catalytic residue at S528 (P = 0)
MVP		0.76
MPC		0.23
ClinPred		0.10	T
GERP RS		-1.8
Varity_R		0.049
gMVP		0.48
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs146173634; hg19: chr12-52841102;