chr12-52487881-C-T

Variant names:

• chr12-52487881-C-T
• NM_005554.4:c.1534G>A

Variant summary

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

The NM_005554.4(KRT6A):​c.1534G>A​(p.Gly512Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT6A NM_005554.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• Publications: 0 publications found

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]

KRT6A Gene-Disease associations (from GenCC):

• pachyonychia congenita 3

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005554.4. 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
	KRT6A	NM_005554.4	MANE Select	c.1534G>A	p.Gly512Arg	missense	Exon 9 of 9	NP_005545.1	A0A0S2Z428

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT6A	ENST00000330722.7	TSL:1 MANE Select	c.1534G>A	p.Gly512Arg	missense	Exon 9 of 9	ENSP00000369317.3	P02538

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.66
Sift	Benign	0.062	T
Sift4G	Uncertain	0.036	D
Polyphen		0.98	D
Vest4		0.28
MutPred		0.41		Gain of catalytic residue at S516 (P = 0)
MVP		0.85
MPC		0.33
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.30
gMVP		0.38
Mutation Taster		=74/26	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

hg19: chr12-52881665; COSMIC: COSV58105619; COSMIC: COSV58105619;