12-52447224-G-A

Variant names:

• chr12-52447224-G-A
• rs539318306
• NM_005555.4:c.1661C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005555.4(KRT6B):​c.1661C>T​(p.Thr554Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KRT6B NM_005555.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.219
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15045238).

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.1661C>T	p.Thr554Ile	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.1661C>T	p.Thr554Ile	missense	Exon 9 of 9	ENSP00000252252.3	P04259

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461780 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111936

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.86
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.22
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.022	D
Polyphen		0.26	B
Vest4		0.21
MutPred		0.32		Gain of sheet (P = 0.0085)
MVP		0.58
MPC		0.19
ClinPred		0.63	D
GERP RS		0.088
Varity_R		0.15
gMVP		0.52
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs539318306; hg19: chr12-52841008;