rs11549949

Positions:

• chr12-52515088-C-A
• chr12-52515088-C-G
• chr12-52515088-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000252242.9(KRT5):​c.1627G>T​(p.Gly543Cys) 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 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. G543S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 28)
• Consequence: KRT5 ENST00000252242.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04

Genes affected

KRT5 (HGNC:6442): (keratin 5) 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. This type II cytokeratin is specifically expressed in the basal layer of the epidermis with family member KRT14. Mutations in these genes have been associated with a complex of diseases termed epidermolysis bullosa simplex. 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT5	NM_000424.4	c.1627G>T	p.Gly543Cys	missense_variant	9/9	ENST00000252242.9	NP_000415.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9	c.1627G>T	p.Gly543Cys	missense_variant	9/9	1	NM_000424.4	ENSP00000252242	P1
KRT5	ENST00000552952.1	n.552G>T		non_coding_transcript_exon_variant	2/2	2
KRT5	ENST00000549511.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Benign	0.83
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.030	D
Polyphen		0.99	D
Vest4		0.55
MutPred		0.41		Gain of sheet (P = 0.0085);
MVP		0.85
MPC		0.23
ClinPred		0.41	T
GERP RS		2.0
Varity_R		0.21
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11549949; hg19: chr12-52908872;