rs11549949

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1627G>A(p.Gly543Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,611,946 control chromosomes in the GnomAD database, including 15,023 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1766 hom., cov: 28)

Exomes 𝑓: 0.13 ( 13257 hom. )

Consequence

KRT5
NM_000424.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.04

Publications

19 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: G2P, Orphanet
epidermolysis bullosa simplex 1A, generalized severe
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
epidermolysis bullosa simplex 2F, with mottled pigmentation
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, 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 2d, generalized, intermediate or severe, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014947951).

BP6

Variant 12-52515088-C-T is Benign according to our data. Variant chr12-52515088-C-T is described in ClinVar as Benign. ClinVar VariationId is 66224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT5	NM_000424.4	MANE Select	c.1627G>A	p.Gly543Ser	missense	Exon 9 of 9	NP_000415.2	P13647

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT5	ENST00000252242.9	TSL:1 MANE Select	c.1627G>A	p.Gly543Ser	missense	Exon 9 of 9	ENSP00000252242.4	P13647
KRT5	ENST00000552952.1	TSL:2	n.552G>A		non_coding_transcript_exon	Exon 2 of 2
ENSG00000303382	ENST00000794060.1		n.465-1492C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

22474

AN:

151064

Hom.:

1760

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.269

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.198

Gnomad EAS

AF:

0.0330

Gnomad SAS

AF:

0.0989

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.223

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.181

GnomAD2 exomes

AF:

0.132

AC:

32459

AN:

244978

AF XY:

0.131

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.151

Gnomad ASJ exome

AF:

0.205

Gnomad EAS exome

AF:

0.0303

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.146

GnomAD4 exome

AF:

0.131

AC:

191366

AN:

1460764

Hom.:

13257

Cov.:

AF XY:

0.130

AC XY:

94628

AN XY:

726616

show subpopulations

African (AFR)

AF:

0.180

AC:

6021

AN:

33466

American (AMR)

AF:

0.154

AC:

6851

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.199

AC:

5201

AN:

26096

East Asian (EAS)

AF:

0.0247

AC:

978

AN:

39674

South Asian (SAS)

AF:

0.102

AC:

8825

AN:

86204

European-Finnish (FIN)

AF:

0.132

AC:

7047

AN:

53292

Middle Eastern (MID)

AF:

0.189

AC:

1091

AN:

5766

European-Non Finnish (NFE)

AF:

0.132

AC:

147062

AN:

1111406

Other (OTH)

AF:

0.137

AC:

8290

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

9828

19657

29485

39314

49142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5260

10520

15780

21040

26300

<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:

0.149

AC:

22505

AN:

151182

Hom.:

1766

Cov.:

AF XY:

0.148

AC XY:

10965

AN XY:

73860

show subpopulations

African (AFR)

AF:

0.177

AC:

7272

AN:

41064

American (AMR)

AF:

0.176

AC:

2677

AN:

15178

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

684

AN:

3460

East Asian (EAS)

AF:

0.0327

AC:

168

AN:

5134

South Asian (SAS)

AF:

0.0988

AC:

466

AN:

4716

European-Finnish (FIN)

AF:

0.122

AC:

1285

AN:

10524

Middle Eastern (MID)

AF:

0.212

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.137

AC:

9273

AN:

67806

Other (OTH)

AF:

0.178

AC:

373

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

880

1760

2640

3520

4400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.140

Hom.:

5116

Bravo

AF:

0.154

TwinsUK

AF:

0.130

AC:

482

ALSPAC

AF:

0.135

AC:

520

ESP6500AA

AF:

0.174

AC:

766

ESP6500EA

AF:

0.140

AC:

1200

ExAC

AF:

0.129

AC:

15616

Asia WGS

AF:

0.0890

AC:

313

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Epidermolysis bullosa simplex (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.31

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.34

PhyloP100

3.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

REVEL

Benign

0.25

Sift

Benign

1.0

Sift4G

Benign

0.29

Polyphen

0.0030

Vest4

0.14

MPC

0.22

ClinPred

0.0066

GERP RS

2.0

Varity_R

0.060

gMVP

0.44

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Computational scores

Splicing

Publications

Other links and lift over