chr12-52520141-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000424.4(KRT5):c.156G>A(p.Ala52Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 1,613,934 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 73 hom., cov: 32)

Exomes 𝑓: 0.0060 ( 192 hom. )

Consequence

KRT5
NM_000424.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.311

Publications

5 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 12-52520141-C-T is Benign according to our data. Variant chr12-52520141-C-T is described in ClinVar as Benign. ClinVar VariationId is 256041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.311 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT5	NM_000424.4 link	c.156G>A	p.Ala52Ala	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.156G>A	p.Ala52Ala	synonymous_variant	Exon 1 of 9	1	NM_000424.4	ENSP00000252242.4		P13647

Frequencies

GnomAD3 genomes

AF:

0.0196

AC:

2978

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0461

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00886

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00262

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.0149

AC:

3732

AN:

250774

AF XY:

0.0125

show subpopulations

Gnomad AFR exome

AF:

0.0459

Gnomad AMR exome

AF:

0.0591

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00827

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00323

Gnomad OTH exome

AF:

0.00997

GnomAD4 exome

AF:

0.00598

AC:

8745

AN:

1461710

Hom.:

192

Cov.:

AF XY:

0.00580

AC XY:

4221

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.0454

AC:

1521

AN:

33480

American (AMR)

AF:

0.0590

AC:

2638

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00892

AC:

354

AN:

39698

South Asian (SAS)

AF:

0.0113

AC:

978

AN:

86258

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.0121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00241

AC:

2683

AN:

1111910

Other (OTH)

AF:

0.00816

AC:

493

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

559

1119

1678

2238

2797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<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:

0.0197

AC:

2998

AN:

152224

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

1521

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0464

AC:

1927

AN:

41532

American (AMR)

AF:

0.0492

AC:

753

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00869

AC:

AN:

5180

South Asian (SAS)

AF:

0.0114

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00262

AC:

178

AN:

68006

Other (OTH)

AF:

0.0185

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

149

297

446

594

743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00550

Hom.:

Bravo

AF:

0.0230

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.00414

EpiControl

AF:

0.00403

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 27, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 12, 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

- -

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

-0.43

CADD

Benign

9.0

(source)

DANN

Benign

0.85

PhyloP100

-0.31

PromoterAI

-0.050

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