12-52519122-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000424.4(KRT5):c.594C>A(p.Thr198Thr) variant causes a synonymous change. The variant allele was found at a frequency of 0.261 in 1,610,090 control chromosomes in the GnomAD database, including 55,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T198T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 4483 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51413 hom. )

Consequence

KRT5
NM_000424.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 4.53

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 12-52519122-G-T is Benign according to our data. Variant chr12-52519122-G-T is described in ClinVar as Benign. ClinVar VariationId is 66277.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT5	NM_000424.4 link	c.594C>A	p.Thr198Thr	synonymous_variant	Exon 2 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.594C>A	p.Thr198Thr	synonymous_variant	Exon 2 of 9	1	NM_000424.4	ENSP00000252242.4

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

34896

AN:

151900

Hom.:

4483

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:

0.247

AC:

60894

AN:

246716

AF XY:

0.246

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.270

Gnomad ASJ exome

AF:

0.262

Gnomad EAS exome

AF:

0.329

Gnomad FIN exome

AF:

0.229

Gnomad NFE exome

AF:

0.266

Gnomad OTH exome

AF:

0.266

GnomAD4 exome

AF:

0.265

AC:

386031

AN:

1458072

Hom.:

51413

Cov.:

AF XY:

0.263

AC XY:

190846

AN XY:

725528

show subpopulations

African (AFR)

AF:

0.126

AC:

4222

AN:

33466

American (AMR)

AF:

0.271

AC:

12104

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

7061

AN:

26106

East Asian (EAS)

AF:

0.388

AC:

15371

AN:

39616

South Asian (SAS)

AF:

0.180

AC:

15495

AN:

86206

European-Finnish (FIN)

AF:

0.237

AC:

12656

AN:

53364

Middle Eastern (MID)

AF:

0.307

AC:

1766

AN:

5750

European-Non Finnish (NFE)

AF:

0.273

AC:

302214

AN:

1108638

Other (OTH)

AF:

0.251

AC:

15142

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

14356

28712

43068

57424

71780

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:

34894

AN:

152018

Hom.:

4483

Cov.:

AF XY:

0.226

AC XY:

16809

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.133

AC:

5509

AN:

41518

American (AMR)

AF:

0.257

AC:

3926

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

925

AN:

3468

East Asian (EAS)

AF:

0.357

AC:

1843

AN:

5168

South Asian (SAS)

AF:

0.180

AC:

865

AN:

4814

European-Finnish (FIN)

AF:

0.236

AC:

2493

AN:

10564

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.273

AC:

18530

AN:

67900

Other (OTH)

AF:

0.236

AC:

498

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1381

2762

4142

5523

6904

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:

0.248

Hom.:

2119

Bravo

AF:

0.231

Asia WGS

AF:

0.234

AC:

814

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6Other: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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

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

Jan 13, 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.

Epidermolysis bullosa simplex 1A, generalized severe;C0432316:Epidermolysis bullosa simplex with mottled pigmentation;C1836284:Epidermolysis bullosa simplex with migratory circinate erythema;C4552092:Dowling-Degos disease 1;C5562009:Epidermolysis bullosa simplex 2B, generalized intermediate;C5562011:Epidermolysis bullosa simplex 2C, localized;C5562014:Epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive;CN301077:Epidermolysis bullosa simplex 2A, generalized severe

Benign:1

Oct 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

4.5

PromoterAI

-0.0080

Neutral

(source)

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over