12-52515040-G-A

Position:

chr12-52515040-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_000424.4(KRT5):c.1675C>T(p.Arg559*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000631 in 1,300,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

KRT5
NM_000424.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2B:1

Conservation

PhyloP100: 2.00

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:

KRT5 (HGNC:):

KRT5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0553 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT5	NM_000424.4 linkuse as main transcript	c.1675C>T	p.Arg559*	stop_gained	9/9	ENST00000252242.9	NP_000415.2	P13647

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9 linkuse as main transcript	c.1675C>T	p.Arg559*	stop_gained	9/9	1	NM_000424.4	ENSP00000252242.4		P13647
KRT5	ENST00000552952.1 linkuse as main transcript	n.600C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000851

AC:

AN:

117466

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000664

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000138

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000578

AC:

AN:

242146

Hom.:

AF XY:

0.0000534

AC XY:

AN XY:

131040

show subpopulations

Gnomad AFR exome

AF:

0.0000625

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000692

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1183020

Hom.:

Cov.:

AF XY:

0.0000562

AC XY:

AN XY:

586770

show subpopulations

Gnomad4 AFR exome

AF:

0.0000360

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000397

Gnomad4 SAS exome

AF:

0.0000414

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000705

Gnomad4 OTH exome

AF:

0.0000647

GnomAD4 genome

AF:

0.0000851

AC:

AN:

117466

Hom.:

Cov.:

AF XY:

0.0000359

AC XY:

AN XY:

55786

show subpopulations

Gnomad4 AFR

AF:

0.0000664

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000138

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000175

Hom.:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2023	Identified in a patient with localized EBS in published literature (Bchetnia et al., 2012); Nonsense variant predicted to result in protein truncation, as the last 32 amino acids are lost; This variant is associated with the following publications: (PMID: 31589614, 21877134) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2017	- -

KRT5-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2023

The KRT5 c.1675C>T variant is predicted to result in premature protein termination (p.Arg559*). This variant was reported to occur de novo in a 51 year old individual with moderate localized epidermolysis bullosa simplex (Bchetnia et al 2012. PubMed ID: 21877134). The c.1675C>T variant is located in the last exon of KRT5 and may not result in nonsense-mediated decay. Other frameshift variants reported in this last exon have been reported with autosomal dominant inheritance, but many of them result in amino acid substitutions and extension of the protein (Yalici-Armagan. 2020. PubMed ID: 31965605; Kim. 2017. PubMed ID: 28561874). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-52908824-G-A). We interpret this variant this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.080

FATHMM_MKL

Benign

0.12

Vest4

0.59

GERP RS

4.6

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.

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