rs11549951

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.351C>T(p.Leu117Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.073 in 1,613,572 control chromosomes in the GnomAD database, including 4,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 492 hom., cov: 31)

Exomes 𝑓: 0.072 ( 4314 hom. )

Consequence

KRT5
NM_000424.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.612

Publications

9 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 12-52519946-G-A is Benign according to our data. Variant chr12-52519946-G-A is described in ClinVar as Benign. ClinVar VariationId is 256043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.612 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.094 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT5	NM_000424.4 link	c.351C>T	p.Leu117Leu	synonymous_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.351C>T	p.Leu117Leu	synonymous_variant	Exon 1 of 9	1	NM_000424.4	ENSP00000252242.4		P13647

Frequencies

GnomAD3 genomes

AF:

0.0782

AC:

11865

AN:

151644

Hom.:

491

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0852

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.0981

Gnomad ASJ

AF:

0.127

Gnomad EAS

AF:

0.0207

Gnomad SAS

AF:

0.0730

Gnomad FIN

AF:

0.0477

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0746

Gnomad OTH

AF:

0.100

GnomAD2 exomes

AF:

0.0741

AC:

18618

AN:

251090

AF XY:

0.0737

show subpopulations

Gnomad AFR exome

AF:

0.0851

Gnomad AMR exome

AF:

0.0916

Gnomad ASJ exome

AF:

0.133

Gnomad EAS exome

AF:

0.0195

Gnomad FIN exome

AF:

0.0456

Gnomad NFE exome

AF:

0.0756

Gnomad OTH exome

AF:

0.0841

GnomAD4 exome

AF:

0.0725

AC:

105935

AN:

1461810

Hom.:

4314

Cov.:

AF XY:

0.0725

AC XY:

52757

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.0832

AC:

2786

AN:

33478

American (AMR)

AF:

0.0943

AC:

4215

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

3431

AN:

26136

East Asian (EAS)

AF:

0.0142

AC:

563

AN:

39698

South Asian (SAS)

AF:

0.0736

AC:

6352

AN:

86254

European-Finnish (FIN)

AF:

0.0475

AC:

2539

AN:

53412

Middle Eastern (MID)

AF:

0.133

AC:

769

AN:

5768

European-Non Finnish (NFE)

AF:

0.0725

AC:

80639

AN:

1111960

Other (OTH)

AF:

0.0769

AC:

4641

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

6019

12038

18056

24075

30094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3000

6000

9000

12000

15000

<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:

0.0783

AC:

11883

AN:

151762

Hom.:

492

Cov.:

AF XY:

0.0779

AC XY:

5777

AN XY:

74150

show subpopulations

African (AFR)

AF:

0.0855

AC:

3537

AN:

41346

American (AMR)

AF:

0.0981

AC:

1497

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

439

AN:

3464

East Asian (EAS)

AF:

0.0206

AC:

106

AN:

5150

South Asian (SAS)

AF:

0.0728

AC:

346

AN:

4750

European-Finnish (FIN)

AF:

0.0477

AC:

503

AN:

10554

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0746

AC:

5070

AN:

67924

Other (OTH)

AF:

0.0988

AC:

208

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

546

1091

1637

2182

2728

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0802

Hom.:

215

Bravo

AF:

0.0810

Asia WGS

AF:

0.0700

AC:

247

AN:

3478

EpiCase

AF:

0.0855

EpiControl

AF:

0.0841

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

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

- -

Jan 23, 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

Jan 12, 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

-0.49

CADD

Benign

2.7

(source)

DANN

Benign

0.90

PhyloP100

-0.61

PromoterAI

-0.012

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