rs57499817

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000424.4(KRT5):c.74C>T(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,762 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: 0.0000027 ( 0 hom. )

Consequence

KRT5
NM_000424.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:2

Conservation

PhyloP100: 3.08

Publications

32 publications found

Variant links:

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

KRT5 links:

ENSG00000303382 (HGNC:):

ENSG00000303382 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

PP5

Variant 12-52520223-G-A is Pathogenic according to our data. Variant chr12-52520223-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 14648.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 link	c.74C>T	p.Pro25Leu	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 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 1 of 9	1	NM_000424.4	ENSP00000252242.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epidermolysis bullosa simplex with mottled pigmentation

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Nov 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and dominant negative are the known mechanisms of disease in this gene and are associated with KRT5-related conditions (DECIPHER, GeneReviews, PMID: 25017986). (I) 0108 - This gene is associated with both recessive and dominant disease. Conditions associated with this gene are mostly autosomal dominant; however rare autosomal recessive cases have been reported, sometimes with more severe phenotypes (OMIM, PMID: 31312705). This variant is well known to cause autosomal dominant Epidermolysis bullosa simplex 2F, with mottled pigmentation (MIM #131960). (I) 0115 - Variants in this gene are known to have variable expressivity, with clinical manifestations varying between members of the same affected family, and of different families (PMID: 22640275). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in greater than 10 unrelated individuals with epidermolysis bullosa simplex with mottled pigmentation (PMID: 11167681, PMID: 8799157, PMID: 22640275, PMID: 26286811, PMID: 23993914, PMID: 20849457, PMID: 33910931, PMID: 24964947, PMID: 26432462). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 04, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that although P25L does not interfere with alignment and assembly of keratin intermediate filaments, it affects the length and uniformity of the resulting filaments, thus explaining the milder blistering phenotype of EBS-MP (Uttam et al., 1996); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect, although this variant resides within the non-helical variable head domain (V1 region) of keratin 5, which is outside the typical keratin hot spots; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31001817, 30690752, 16581562, 22640275, 21623745, 21375516, 20199538, 20923750, 8799157, 16882168, 16098032, 15827748, 11167681, 10494094, 9129237, 26286811, 15030360, 24964947, 22161089, 23889190, 17229601) -

Sep 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 25 of the KRT5 protein (p.Pro25Leu). 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: 8799157, 15030360, 16098032, 16581562, 17229601). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Pro24Leu. ClinVar contains an entry for this variant (Variation ID: 14648). 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 not expected to disrupt KRT5 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Mar 31, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.74C>T (p.P25L) alteration is located in exon 1 (coding exon 1) of the KRT5 gene. This alteration results from a C to T substitution at nucleotide position 74, causing the proline (P) at amino acid position 25 to be replaced by a leucine (L). for autosomal dominant KRT5-related epidermolysis bullosa simplex; however, its clinical significance for autosomal recessive KRT5-related epidermolysis bullosa simplex and autosomal dominant Dowling-Degos disease is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was identified in one or more individuals with features consistent with autosomal dominant KRT5-related epidermolysis bullosa simplex (Uttam, 1996; Hamada, 2004; Pfendner, 2005; Pascucci, 2006; Echeverría-García, 2013) and segregated with disease in at least one family (Uttam, 1996). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

KRT5-related disorder

Pathogenic:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The KRT5 c.74C>T variant is predicted to result in the amino acid substitution p.Pro25Leu. This variant has been reported in individuals with epidermolysis bullosa simplex (EBS) and the affected family members (see for example, Uttam et al. 1996. PubMed ID: 8799157, reported as P24L; Pascucci et al. 2006. PubMed ID: 17229601; Pfendner et al. 2005. PubMed ID: 16098032; Mariath et al. 2019. PubMed ID: 31001817). This variant has also been reported as de novo in an individual with EBS (Table S1, Chen et al. 2023. PubMed ID: 36287101). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

Epidermolysis bullosa simplex

Pathogenic:1

Feb 26, 2018

Biomedical Innovation Departament, CIEMAT

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.73

D;.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

0.0090

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.0

M;.;.

PhyloP100

3.1

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Uncertain

0.41

Sift

Benign

0.086

T;T;D

Sift4G

Benign

0.18

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.71

MutPred

0.76

Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);

MVP

0.69

MPC

0.63

ClinPred

0.99

GERP RS

5.1

PromoterAI

0.010

Neutral

(source)

Varity_R

0.17

gMVP

0.54

Mutation Taster

=33/67

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over