12-52519884-C-T

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.413G>A(p.Gly138Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0691 in 1,613,822 control chromosomes in the GnomAD database, including 4,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 300 hom., cov: 31)

Exomes 𝑓: 0.071 ( 4099 hom. )

Consequence

KRT5
NM_000424.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.33

Publications

62 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: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000424.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0046600103).

BP6

Variant 12-52519884-C-T is Benign according to our data. Variant chr12-52519884-C-T is described in ClinVar as Benign. ClinVar VariationId is 66234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT5	NM_000424.4 link	c.413G>A	p.Gly138Glu	missense_variant	Exon 1 of 9	ENST00000252242.9	NP_000415.2	P13647

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9 link	c.413G>A	p.Gly138Glu	missense_variant	Exon 1 of 9	1	NM_000424.4	ENSP00000252242.4		P13647

Frequencies

GnomAD3 genomes

AF:

0.0523

AC:

7939

AN:

151822

Hom.:

299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0127

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.0283

Gnomad ASJ

AF:

0.0471

Gnomad EAS

AF:

0.000967

Gnomad SAS

AF:

0.0533

Gnomad FIN

AF:

0.0898

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0809

Gnomad OTH

AF:

0.0431

GnomAD2 exomes

AF:

0.0565

AC:

14213

AN:

251454

AF XY:

0.0585

show subpopulations

Gnomad AFR exome

AF:

0.0116

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0476

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.0979

Gnomad NFE exome

AF:

0.0782

Gnomad OTH exome

AF:

0.0552

GnomAD4 exome

AF:

0.0709

AC:

103650

AN:

1461882

Hom.:

4099

Cov.:

AF XY:

0.0706

AC XY:

51365

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0108

AC:

362

AN:

33480

American (AMR)

AF:

0.0203

AC:

907

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0458

AC:

1196

AN:

26134

East Asian (EAS)

AF:

0.000227

AC:

AN:

39700

South Asian (SAS)

AF:

0.0524

AC:

4519

AN:

86258

European-Finnish (FIN)

AF:

0.0974

AC:

5204

AN:

53420

Middle Eastern (MID)

AF:

0.0496

AC:

286

AN:

5768

European-Non Finnish (NFE)

AF:

0.0785

AC:

87320

AN:

1112004

Other (OTH)

AF:

0.0637

AC:

3847

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

6299

12599

18898

25198

31497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3130

6260

9390

12520

15650

<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:

0.0523

AC:

7945

AN:

151940

Hom.:

300

Cov.:

AF XY:

0.0512

AC XY:

3802

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.0126

AC:

524

AN:

41444

American (AMR)

AF:

0.0283

AC:

432

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0471

AC:

163

AN:

3464

East Asian (EAS)

AF:

0.000970

AC:

AN:

5156

South Asian (SAS)

AF:

0.0544

AC:

258

AN:

4746

European-Finnish (FIN)

AF:

0.0898

AC:

950

AN:

10580

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0809

AC:

5498

AN:

67960

Other (OTH)

AF:

0.0427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

367

734

1102

1469

1836

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0679

Hom.:

2013

Bravo

AF:

0.0437

TwinsUK

AF:

0.0823

AC:

305

ALSPAC

AF:

0.0802

AC:

309

ESP6500AA

AF:

0.0161

AC:

ESP6500EA

AF:

0.0743

AC:

639

ExAC

AF:

0.0582

AC:

7061

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0762

EpiControl

AF:

0.0742

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

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: 32885477, 17549391, 27884173, 20981092, 19578363, 20849457, 23746086) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;T;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;D;D

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Uncertain

0.0020

MutationAssessor

Pathogenic

3.6

H;.;.

PhyloP100

5.3

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.2

D;D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0090

D;D;D

Sift4G

Uncertain

0.0080

D;.;D

Polyphen

0.96

D;.;.

Vest4

0.35

MPC

0.95

ClinPred

0.095

GERP RS

5.5

PromoterAI

0.034

Neutral

(source)

Varity_R

0.82

gMVP

0.86

Mutation Taster

=75/25

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over