NM_000424.4:c.591C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000424.4(KRT5):c.591C>A(p.Asp197Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,610,082 control chromosomes in the GnomAD database, including 55,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D197N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 4479 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51436 hom. )

Consequence

KRT5
NM_000424.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.963

Publications

28 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:

ENSG00000303401 (HGNC:):

ENSG00000303401 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000424.4

BP4

Computational evidence support a benign effect (MetaRNN=0.004725188).

BP6

Variant 12-52519125-G-T is Benign according to our data. Variant chr12-52519125-G-T is described in ClinVar as Benign. ClinVar VariationId is 66275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

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.591C>A	p.Asp197Glu	missense	Exon 2 of 9	NP_000415.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KRT5	ENST00000252242.9	TSL:1 MANE Select	c.591C>A	p.Asp197Glu	missense	Exon 2 of 9	ENSP00000252242.4
KRT5	ENST00000552629.5	TSL:1	n.689C>A		non_coding_transcript_exon	Exon 2 of 7
KRT5	ENST00000549420.1	TSL:5	c.261C>A	p.Asp87Glu	missense	Exon 3 of 5	ENSP00000447209.1

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

34888

AN:

151888

Hom.:

4479

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.267

Gnomad EAS

AF:

0.356

Gnomad SAS

AF:

0.180

Gnomad FIN

AF:

0.236

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.273

Gnomad OTH

AF:

0.237

GnomAD2 exomes

AF:

0.245

AC:

60185

AN:

245436

AF XY:

0.244

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.269

Gnomad ASJ exome

AF:

0.262

Gnomad EAS exome

AF:

0.327

Gnomad FIN exome

AF:

0.228

Gnomad NFE exome

AF:

0.264

Gnomad OTH exome

AF:

0.266

GnomAD4 exome

AF:

0.265

AC:

386047

AN:

1458076

Hom.:

51436

Cov.:

AF XY:

0.263

AC XY:

190850

AN XY:

725542

show subpopulations

African (AFR)

AF:

0.126

AC:

4219

AN:

33462

American (AMR)

AF:

0.271

AC:

12114

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

7060

AN:

26108

East Asian (EAS)

AF:

0.388

AC:

15360

AN:

39596

South Asian (SAS)

AF:

0.180

AC:

15494

AN:

86204

European-Finnish (FIN)

AF:

0.237

AC:

12656

AN:

53362

Middle Eastern (MID)

AF:

0.307

AC:

1766

AN:

5752

European-Non Finnish (NFE)

AF:

0.273

AC:

302240

AN:

1108676

Other (OTH)

AF:

0.251

AC:

15138

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

14294

28589

42883

57178

71472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10102

20204

30306

40408

50510

<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

AF:

0.230

AC:

34886

AN:

152006

Hom.:

4479

Cov.:

AF XY:

0.226

AC XY:

16806

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.133

AC:

5508

AN:

41512

American (AMR)

AF:

0.257

AC:

3926

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

925

AN:

3466

East Asian (EAS)

AF:

0.357

AC:

1844

AN:

5170

South Asian (SAS)

AF:

0.180

AC:

866

AN:

4818

European-Finnish (FIN)

AF:

0.236

AC:

2489

AN:

10564

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.273

AC:

18527

AN:

67894

Other (OTH)

AF:

0.235

AC:

496

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1359

2718

4076

5435

6794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

376

752

1128

1504

1880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.260

Hom.:

1725

Bravo

AF:

0.231

TwinsUK

AF:

0.271

AC:

1005

ALSPAC

AF:

0.271

AC:

1044

ExAC

AF:

0.243

AC:

29462

Asia WGS

AF:

0.234

AC:

814

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31965605, 19578363)

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Epidermolysis bullosa simplex

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.33

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.034

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.9

PhyloP100

0.96

PrimateAI

Uncertain

0.58

PROVEAN

Benign

1.2

REVEL

Uncertain

0.36

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.030

Vest4

0.045

MutPred

0.13

Loss of ubiquitination at K199 (P = 0.0795)

MPC

0.24

ClinPred

0.014

GERP RS

2.4

PromoterAI

-0.0022

Neutral

(source)

Varity_R

0.060

gMVP

0.50

Mutation Taster

=87/13

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over