12-52447245-G-T

Variant names:

• chr12-52447245-G-T
• NM_005555.4:c.1640C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005555.4(KRT6B):​c.1640C>A​(p.Ser547Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S547C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KRT6B NM_005555.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT6B	NM_005555.4	c.1640C>A	p.Ser547Tyr	missense_variant	Exon 9 of 9	ENST00000252252.4	NP_005546.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT6B	ENST00000252252.4	c.1640C>A	p.Ser547Tyr	missense_variant	Exon 9 of 9	1	NM_005555.4	ENSP00000252252.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461728 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.064	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.062	T
Polyphen		0.061	B
Vest4		0.50
MutPred		0.39		Gain of catalytic residue at G544 (P = 2e-04);
MVP		0.88
MPC		0.22
ClinPred		0.96	D
GERP RS		1.9
Varity_R		0.30
gMVP		0.64

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-52841029;