rs58058996

Variant names:

• chr12-52519815-A-C
• rs58058996
• NM_000424.4:c.482T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-52519815-A-C
• chr12-52519815-A-G
• chr12-52519815-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000424.4(KRT5):​c.482T>G​(p.Ile161Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.33

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 12-52519815-A-C is Pathogenic according to our data. Variant chr12-52519815-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 14640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT5	NM_000424.4	c.482T>G	p.Ile161Ser	missense_variant	Exon 1 of 9	ENST00000252242.9	NP_000415.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9	c.482T>G	p.Ile161Ser	missense_variant	Exon 1 of 9	1	NM_000424.4	ENSP00000252242.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 03, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Located in the highly conserved head domain, preceding the helix initiation motif; keratin gene variants affecting the residues at the head domain in type II keratins are known to interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility, blistering, and/or hyperkeratosis (Chamcheu et al., 2011); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7537780, 29334134, 7688477, 27065010, 16098032, 27535533) -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 161 of the KRT5 protein (p.Ile161Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant epidermolysis bullosa simplex (PMID: 7537780, 7688477, 16098032). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14640). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KRT5 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Epidermolysis bullosa simplex 2C, localized Pathogenic:1

Aug 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Epidermolysis bullosa simplex 1C, localized Pathogenic:1

Jun 14, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PS4, PM5_Supporting, PP3, PM1, PM2 -

KRT5-related disorder Pathogenic:1

Aug 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KRT5 c.482T>G variant is predicted to result in the amino acid substitution p.Ile161Ser. This variant has been reported in many individuals with autosomal dominant epidermolysis bullosa, and has shown segregation in affected family members (Chan et al. 1993. PubMed ID: 7688477; Ehrlich et al. 1995. PubMed ID: 7537780; Pfendner et al. 2005. PubMed ID: 16098032). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;.;T
Polyphen		1.0	D;.;.
Vest4		0.93
MutPred		0.88		Gain of disorder (P = 0.0028);.;.;
MVP		0.98
MPC		0.89
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.94
gMVP		0.98

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: rs58058996; hg19: chr12-52913599;