chr12-52518984-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000424.4(KRT5):c.732G>A(p.Leu244Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,614,044 control chromosomes in the GnomAD database, including 15,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1804 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13225 hom. )

Consequence

KRT5
NM_000424.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.589

Publications

10 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 12-52518984-C-T is Benign according to our data. Variant chr12-52518984-C-T is described in ClinVar as Benign. ClinVar VariationId is 66283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.589 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT5	NM_000424.4 link	c.732G>A	p.Leu244Leu	synonymous_variant	Exon 2 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.732G>A	p.Leu244Leu	synonymous_variant	Exon 2 of 9	1	NM_000424.4	ENSP00000252242.4		P13647

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

22815

AN:

152044

Hom.:

1798

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.269

Gnomad AMR

AF:

0.178

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.0333

Gnomad SAS

AF:

0.101

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.181

GnomAD2 exomes

AF:

0.132

AC:

33176

AN:

251440

AF XY:

0.131

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.151

Gnomad ASJ exome

AF:

0.203

Gnomad EAS exome

AF:

0.0302

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.131

AC:

191115

AN:

1461882

Hom.:

13225

Cov.:

AF XY:

0.130

AC XY:

94506

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.180

AC:

6015

AN:

33480

American (AMR)

AF:

0.153

AC:

6861

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

5176

AN:

26136

East Asian (EAS)

AF:

0.0246

AC:

978

AN:

39700

South Asian (SAS)

AF:

0.101

AC:

8749

AN:

86258

European-Finnish (FIN)

AF:

0.132

AC:

7065

AN:

53420

Middle Eastern (MID)

AF:

0.189

AC:

1093

AN:

5768

European-Non Finnish (NFE)

AF:

0.132

AC:

146890

AN:

1112002

Other (OTH)

AF:

0.137

AC:

8288

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

11730

23460

35189

46919

58649

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5250

10500

15750

21000

26250

<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:

0.150

AC:

22847

AN:

152162

Hom.:

1804

Cov.:

AF XY:

0.150

AC XY:

11161

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.179

AC:

7424

AN:

41500

American (AMR)

AF:

0.178

AC:

2722

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

681

AN:

3466

East Asian (EAS)

AF:

0.0330

AC:

171

AN:

5178

South Asian (SAS)

AF:

0.101

AC:

489

AN:

4824

European-Finnish (FIN)

AF:

0.125

AC:

1329

AN:

10594

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.138

AC:

9349

AN:

67986

Other (OTH)

AF:

0.178

AC:

376

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

973

1946

2920

3893

4866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.133

Hom.:

2411

Bravo

AF:

0.154

Asia WGS

AF:

0.0890

AC:

311

AN:

3478

EpiCase

AF:

0.150

EpiControl

AF:

0.147

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

6.7

(source)

DANN

Uncertain

1.0

PhyloP100

0.59

PromoterAI

-0.013

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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