12-52447788-C-G

Variant names:

• chr12-52447788-C-G
• rs60627726
• NM_005555.4:c.1414G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_005555.4(KRT6B):​c.1414G>C​(p.Glu472Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. E472K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT6B NM_005555.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-52447788-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT6B	NM_005555.4	c.1414G>C	p.Glu472Gln	missense_variant	Exon 7 of 9	ENST00000252252.4	NP_005546.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT6B	ENST00000252252.4	c.1414G>C	p.Glu472Gln	missense_variant	Exon 7 of 9	1	NM_005555.4	ENSP00000252252.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.43
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.80		Gain of catalytic residue at L476 (P = 0.0056);
MVP		0.93
MPC		0.67
ClinPred		0.99	D
GERP RS		0.88
Varity_R		0.82
gMVP		0.88
Mutation Taster		=55/45	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: rs60627726; hg19: chr12-52841572;