rs886039403

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate

The NM_000424.4(KRT5):​c.555+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

KRT5
NM_000424.4 splice_donor

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.86
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 12-52519741-C-T is Pathogenic according to our data. Variant chr12-52519741-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265218.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KRT5NM_000424.4 linkuse as main transcriptc.555+1G>A splice_donor_variant ENST00000252242.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KRT5ENST00000252242.9 linkuse as main transcriptc.555+1G>A splice_donor_variant 1 NM_000424.4 P1
KRT5ENST00000552629.5 linkuse as main transcriptn.653+1G>A splice_donor_variant, non_coding_transcript_variant 1
KRT5ENST00000549420.1 linkuse as main transcriptc.225+1G>A splice_donor_variant 5
KRT5ENST00000551275.1 linkuse as main transcript downstream_gene_variant 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 13, 2022Canonical splice site variant expected to result in aberrant splicing; Sequencing of cDNA from cultured keratinocytes demonstrates that this variant leads to use of a cryptic donor splice site located 66 nucleotides upstream from the normal donor splice site of intron 1, resulting in a shortened polypeptide that disrupts normal keratin filament assembly (Rugg et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 10234505, 29932457, 31001817, 32484238) -
Epidermolysis bullosa simplex 2A, generalized severe Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 1999- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
32
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Uncertain
0.95
D
MutationTaster
Benign
1.0
D
GERP RS
5.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.99
Position offset: 1

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: rs886039403; hg19: chr12-52913525; API