chr17-40822120-G-A

Position:

• chr17-40822120-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000421.5(KRT10):​c.466C>T​(p.Arg156Cys) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT10 NM_000421.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 8.10

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000421.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-40822119-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-40822120-G-A is Pathogenic according to our data. Variant chr17-40822120-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-40822120-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT10	NM_000421.5	c.466C>T	p.Arg156Cys	missense_variant	1/8	ENST00000269576.6
KRT10-AS1	NR_160888.1	n.64+2912G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT10	ENST00000269576.6	c.466C>T	p.Arg156Cys	missense_variant	1/8	1	NM_000421.5	P2
KRT10-AS1	ENST00000301665.9	n.108+2912G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 26, 2020	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg156 amino acid residue in KRT10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1381287, 21271994). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KRT10 function (PMID: 7512983, 26176760). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRT10 protein function. ClinVar contains an entry for this variant (Variation ID: 14576). This missense change has been observed in individual(s) with autosomal dominant KRT10 related conditions (PMID: 21271994, 22930352, 28532675). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the KRT10 protein (p.Arg156Cys). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2021	Located within the 1A domain helix initiation motif that is intolerant to change; variants affecting the residues at the ends of the central rod domains of the keratin proteins (helix initiation and termination motifs) interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility and/or hyperkeratosis (Chamcheu et al., 2011); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11990254, 17683385, 7509230, 7512983, 7526210, 28532675, 27722766, 22930352, 27535533, 31953843, 18033728, 24077912, 33081034) -

Epidermolytic nevus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Oct 10, 2023

The KRT10 c.466C>T (Arg156Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected by ichthyosis (Paller AS et al., PMID: 7526210; Cheraghlou S et al., PMID: 32045015; Bygum A et al., PMID: 22930352; Kono M et al., PMID: 28532675; Syder AJ et al., PMID: 7512983; Mirza H et al., PMID: 26176760; Haruna K et al., PMID: 17683385; Rothnagel JA et al., PMID: 7509230; Diociaiuti A et al., PMID: 33081034). This variant has been reported in the ClinVar database as a pathogenic germline variant by multiple submitters and a likely pathogenic somatic variant by one submitter (ClinVar ID: 14576) and, in one case, in the cancer database COSMIC (ID: COSV99509833). This variant is absent from the general population, indicating that it is not a common variant (gnomAD v.3.1.2). The KRT10 c.466C>T (Arg156Cys) variant resides within an intermediate filament rod domain, amino acids 145-454, of KRT10 that is defined as a critical functional domain (Porter RM et al., PMID: 12711220; Rothnagel JA et al., PMID: 1380725). Functional studies show that this variant results in filament assembly disruption, leading to cell fragility (Syder AJ et al., PMID: 7512983; Mirza H et al., PMID: 26176760). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KRT10 function. Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the KRT10 c.466C>T (Arg156Cys) variant is classified as pathogenic. -

Epidermolytic hyperkeratosis 2A, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1994

- -

KRT10-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2022

The KRT10 c.466C>T variant is predicted to result in the amino acid substitution p.Arg156Cys. This variant has been frequently reported in individuals with epidermolytic hyperkeratosis (see for example Syder et al. 1994. PubMed ID: 7512983; Saeki et al. 2002. PubMed ID: 11990254; Haruna et al. 2007. PubMed ID: 17683385; Bygum et al. 2013. PubMed ID: 22930352; Severino-Freire et al. 2017. PubMed ID: 27722766; Kono et al. 2017. PubMed ID: 28532675; Cheng et al. 2020. PubMed ID: 31953843). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Epidermolytic acanthoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Feb 19, 2020

- -

Epidermolytic ichthyosis;C1843463:Annular epidermolytic ichthyosis;C3665704:Congenital reticular ichthyosiform erythroderma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.98		Gain of catalytic residue at L157 (P = 0.0192);
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.71
gMVP		0.98

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

Other links and lift over

dbSNP: rs58852768; hg19: chr17-38978372; COSMIC: COSV99509833; COSMIC: COSV99509833;