NM_000424.4:c.1627G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT5	NM_000424.4 link	c.1627G>A	p.Gly543Ser	missense_variant	Exon 9 of 9	ENST00000252242.9	NP_000415.2	P13647

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRT5	ENST00000252242.9 link	c.1627G>A	p.Gly543Ser	missense_variant	Exon 9 of 9	1	NM_000424.4	ENSP00000252242.4	P13647
KRT5	ENST00000552952.1 link	n.552G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
KRT5	ENST00000549511.5 link	n.*25G>A		downstream_gene_variant		2

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

GnomAD3 exomes

AF:

0.132

AC:

32459

AN:

244978

Hom.:

2406

AF XY:

0.131

AC XY:

17428

AN XY:

132766

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 SAS exome

AF:

0.105

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

Gnomad4 AFR exome

AF:

0.180

Gnomad4 AMR exome

AF:

0.154

Gnomad4 ASJ exome

AF:

0.199

Gnomad4 EAS exome

AF:

0.0247

Gnomad4 SAS exome

AF:

0.102

Gnomad4 FIN exome

AF:

0.132

Gnomad4 NFE exome

AF:

0.132

Gnomad4 OTH exome

AF:

0.137

GnomAD4 genome

AF:

0.149

AC:

22505

AN:

151182

Hom.:

1766

Cov.:

AF XY:

0.148

AC XY:

10965

AN XY:

73860

show subpopulations

Gnomad4 AFR

AF:

0.177

Gnomad4 AMR

AF:

0.176

Gnomad4 ASJ

AF:

0.198

Gnomad4 EAS

AF:

0.0327

Gnomad4 SAS

AF:

0.0988

Gnomad4 FIN

AF:

0.122

Gnomad4 NFE

AF:

0.137

Gnomad4 OTH

AF:

0.178

Alfa

AF:

0.141

Hom.:

2505

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

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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Benign

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over