17-40819163-T-G

Variant names:

• chr17-40819163-T-G
• rs587776815
• NM_000421.5:c.1374-2A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000421.5(KRT10):​c.1374-2A>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: KRT10 NM_000421.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.104

Genes affected

KRT10 (HGNC:6413): (keratin 10) This gene encodes a member of the type I (acidic) cytokeratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. Mutations in this gene are associated with epidermolytic hyperkeratosis. This gene is located within a cluster of keratin family members on chromosome 17q21. [provided by RefSeq, Jul 2008]

KRT10-AS1 (HGNC:28305): (KRT10 antisense RNA 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.21367522 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.5, offset of -31, new splice context is: ccaccgttttccaacgttAGaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-40819163-T-G is Pathogenic according to our data. Variant chr17-40819163-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 449615.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT10	NM_000421.5	c.1374-2A>C		splice_acceptor_variant, intron_variant	Intron 6 of 7	ENST00000269576.6	NP_000412.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT10	ENST00000269576.6	c.1374-2A>C		splice_acceptor_variant, intron_variant	Intron 6 of 7	1	NM_000421.5	ENSP00000269576.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 25, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While the c.1374-2 A>C variant in the KRT10 gene has not been published previously, several other nucleotide substitutions altering the same splice acceptor site in intron 6 (c.1374-2A>G; c.1374-1G>A; c.1374-1G>C) have been reported as de novo events or inherited from an affected parent in many patients with ichthyosis with confetti (Choate et al. 2010; Diociaiuti et al. 2014; Xiong et al. 2015). Multiple in silico splice algorithms concur that the c.1374-2 A>C variant likely destroys this canonical splice acceptor site, causing abnormal gene splicing, and protein truncation or nonsense-mediated mRNA decay. The intron 6 acceptor splice site is a mutational hotspot in ichthyosis with confetti, and all pathogenic variants for this disorder are predicted to produce a shift in the reading frame that creates the same abnormal, arginine-rich C-terminus of keratin 10 that confers mislocalization of the protein to the nucleolus (Choate et al. 2010). Moreover, c.1374-2 A>C was not observed in approximately 4,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a benign variant in these populations. In summary, we interpret c.1374-2 A>C as a pathogenic variant associated with ichthyosis with confetti (IWC) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Benign	0.87
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.013
FATHMM_MKL	Benign	0.076	N
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: -10
DS_AL_spliceai		0.91		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776815; hg19: chr17-38975415;