12-52519137-G-C

Position:

• chr12-52519137-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Moderate

The NM_000424.4(KRT5):​c.579C>G​(p.Asn193Lys) 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. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 4.94

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 Pathogenic. Variant got 14 ACMG points.

• PS1: Transcript NM_000424.4 (KRT5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a region_of_interest Coil 1A (size 35) in uniprot entity K2C5_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000424.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 12-52519137-G-C is Pathogenic according to our data. Variant chr12-52519137-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14644.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT5	NM_000424.4	c.579C>G	p.Asn193Lys	missense_variant	2/9	ENST00000252242.9	NP_000415.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9	c.579C>G	p.Asn193Lys	missense_variant	2/9	1	NM_000424.4	ENSP00000252242.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epidermolysis bullosa simplex 2C, localized Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1996

- -

Epidermolysis bullosa simplex Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Biomedical Innovation Departament, CIEMAT

Nov 12, 2014

- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.95		Gain of MoRF binding (P = 0.041);.;
MVP		0.99
MPC		0.89
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.89
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs60586163; hg19: chr12-52912921;