12-52519125-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000424.4(KRT5):​c.591C>A​(p.Asp197Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,610,082 control chromosomes in the GnomAD database, including 55,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4479 hom., cov: 32)
Exomes 𝑓: 0.26 ( 51436 hom. )

Consequence

KRT5
NM_000424.4 missense

Scores

2
16

Clinical Significance

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

Conservation

PhyloP100: 0.963
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1
In a region_of_interest Coil 1A (size 35) in uniprot entity K2C5_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000424.4
BP4
Computational evidence support a benign effect (MetaRNN=0.004725188).
BP6
Variant 12-52519125-G-T is Benign according to our data. Variant chr12-52519125-G-T is described in ClinVar as [Benign]. Clinvar id is 66275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KRT5NM_000424.4 linkuse as main transcriptc.591C>A p.Asp197Glu missense_variant 2/9 ENST00000252242.9 NP_000415.2 P13647

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KRT5ENST00000252242.9 linkuse as main transcriptc.591C>A p.Asp197Glu missense_variant 2/91 NM_000424.4 ENSP00000252242.4 P13647

Frequencies

GnomAD3 genomes
AF:
0.230
AC:
34888
AN:
151888
Hom.:
4479
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.133
Gnomad AMI
AF:
0.230
Gnomad AMR
AF:
0.258
Gnomad ASJ
AF:
0.267
Gnomad EAS
AF:
0.356
Gnomad SAS
AF:
0.180
Gnomad FIN
AF:
0.236
Gnomad MID
AF:
0.307
Gnomad NFE
AF:
0.273
Gnomad OTH
AF:
0.237
GnomAD3 exomes
AF:
0.245
AC:
60185
AN:
245436
Hom.:
7471
AF XY:
0.244
AC XY:
32447
AN XY:
132766
show subpopulations
Gnomad AFR exome
AF:
0.114
Gnomad AMR exome
AF:
0.269
Gnomad ASJ exome
AF:
0.262
Gnomad EAS exome
AF:
0.327
Gnomad SAS exome
AF:
0.174
Gnomad FIN exome
AF:
0.228
Gnomad NFE exome
AF:
0.264
Gnomad OTH exome
AF:
0.266
GnomAD4 exome
AF:
0.265
AC:
386047
AN:
1458076
Hom.:
51436
Cov.:
80
AF XY:
0.263
AC XY:
190850
AN XY:
725542
show subpopulations
Gnomad4 AFR exome
AF:
0.126
Gnomad4 AMR exome
AF:
0.271
Gnomad4 ASJ exome
AF:
0.270
Gnomad4 EAS exome
AF:
0.388
Gnomad4 SAS exome
AF:
0.180
Gnomad4 FIN exome
AF:
0.237
Gnomad4 NFE exome
AF:
0.273
Gnomad4 OTH exome
AF:
0.251
GnomAD4 genome
AF:
0.230
AC:
34886
AN:
152006
Hom.:
4479
Cov.:
32
AF XY:
0.226
AC XY:
16806
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.133
Gnomad4 AMR
AF:
0.257
Gnomad4 ASJ
AF:
0.267
Gnomad4 EAS
AF:
0.357
Gnomad4 SAS
AF:
0.180
Gnomad4 FIN
AF:
0.236
Gnomad4 NFE
AF:
0.273
Gnomad4 OTH
AF:
0.235
Alfa
AF:
0.260
Hom.:
1725
Bravo
AF:
0.231
TwinsUK
AF:
0.271
AC:
1005
ALSPAC
AF:
0.271
AC:
1044
ExAC
AF:
0.243
AC:
29462
Asia WGS
AF:
0.234
AC:
814
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
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -
not provided, no classification providedliterature onlyEpithelial Biology; Institute of Medical Biology, Singapore-- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 31965605, 19578363) -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Epidermolysis bullosa simplex Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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
0.16
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
15
DANN
Benign
0.67
DEOGEN2
Benign
0.33
T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.64
FATHMM_MKL
Benign
0.64
D
LIST_S2
Benign
0.034
T;T
MetaRNN
Benign
0.0047
T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
-1.9
N;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
1.2
N;N
REVEL
Uncertain
0.36
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;.
Polyphen
0.030
B;.
Vest4
0.045
MutPred
0.13
Loss of ubiquitination at K199 (P = 0.0795);.;
MPC
0.24
ClinPred
0.014
T
GERP RS
2.4
Varity_R
0.060
gMVP
0.50

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

LitVar

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

Other links and lift over

dbSNP: rs641615; hg19: chr12-52912909; COSMIC: COSV52858847; COSMIC: COSV52858847; API