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. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I161N) has been classified 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
• Publications: 6 publications found

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]

KRT5 Gene-Disease associations (from GenCC):

• Dowling-Degos disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• epidermolysis bullosa simplex 1A, generalized severe

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics
• epidermolysis bullosa simplex 2F, with mottled pigmentation

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia, G2P
• Dowling-Degos disease 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• epidermolysis bullosa simplex 1B, generalized intermediate

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 1C, localized

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 2B, generalized intermediate

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 2E, with migratory circinate erythema

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000303382 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000424.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-52519815-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 426998.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 VariationId is 14640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000424.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT5	NM_000424.4	MANE Select	c.482T>G	p.Ile161Ser	missense	Exon 1 of 9	NP_000415.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT5	ENST00000252242.9	TSL:1 MANE Select	c.482T>G	p.Ile161Ser	missense	Exon 1 of 9	ENSP00000252242.4
	KRT5	ENST00000552629.5	TSL:1	n.580T>G		non_coding_transcript_exon	Exon 1 of 7
	KRT5	ENST00000549420.1	TSL:5	c.152T>G	p.Ile51Ser	missense	Exon 2 of 5	ENSP00000447209.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

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)

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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

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.

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

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
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
Mutation Taster		=21/79	disease causing (ClinVar)

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

dbSNP: rs58058996; hg19: chr12-52913599;