12-52519086-A-G

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.630T>C(p.Thr210Thr) 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 1,613,998 control chromosomes in the GnomAD database, including 15,131 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. T210T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 1817 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13314 hom. )

Consequence

KRT5
NM_000424.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.82

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: 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:

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 (REVEL=0.009).

BP6

Variant 12-52519086-A-G is Benign according to our data. Variant chr12-52519086-A-G is described in ClinVar as Benign. ClinVar VariationId is 66282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.82 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 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.630T>C	p.Thr210Thr	synonymous	Exon 2 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.630T>C	p.Thr210Thr	synonymous	Exon 2 of 9	ENSP00000252242.4	P13647
KRT5	ENST00000552629.5	TSL:1	n.728T>C		non_coding_transcript_exon	Exon 2 of 7
KRT5	ENST00000551188.5	TSL:5	c.31T>C	p.Cys11Arg	missense	Exon 1 of 6	ENSP00000449783.1	H0YIN9

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

22880

AN:

152012

Hom.:

1811

Cov.:

show subpopulations

Gnomad AFR

AF:

0.179

Gnomad AMI

AF:

0.270

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.198

Gnomad EAS

AF:

0.0336

Gnomad SAS

AF:

0.104

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:

33315

AN:

251456

AF XY:

0.131

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.151

Gnomad ASJ exome

AF:

0.205

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:

191748

AN:

1461868

Hom.:

13314

Cov.:

AF XY:

0.130

AC XY:

94857

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.180

AC:

6016

AN:

33480

American (AMR)

AF:

0.154

AC:

6873

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.199

AC:

5207

AN:

26136

East Asian (EAS)

AF:

0.0247

AC:

980

AN:

39700

South Asian (SAS)

AF:

0.104

AC:

8939

AN:

86256

European-Finnish (FIN)

AF:

0.132

AC:

7070

AN:

53420

Middle Eastern (MID)

AF:

0.190

AC:

1094

AN:

5766

European-Non Finnish (NFE)

AF:

0.132

AC:

147253

AN:

1111998

Other (OTH)

AF:

0.138

AC:

8316

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

11322

22644

33966

45288

56610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5264

10528

15792

21056

26320

<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:

0.151

AC:

22912

AN:

152130

Hom.:

1817

Cov.:

AF XY:

0.150

AC XY:

11188

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.179

AC:

7439

AN:

41486

American (AMR)

AF:

0.179

AC:

2736

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

686

AN:

3466

East Asian (EAS)

AF:

0.0333

AC:

172

AN:

5172

South Asian (SAS)

AF:

0.104

AC:

499

AN:

4804

European-Finnish (FIN)

AF:

0.125

AC:

1327

AN:

10592

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.138

AC:

9369

AN:

68002

Other (OTH)

AF:

0.178

AC:

376

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1006

2012

3018

4024

5030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

242

484

726

968

1210

<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:

0.146

Hom.:

704

Bravo

AF:

0.154

Asia WGS

AF:

0.0900

AC:

314

AN:

3476

EpiCase

AF:

0.150

EpiControl

AF:

0.147

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

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.60

(source)

DANN

Benign

0.61

PhyloP100

-1.8

PromoterAI

0.0050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over