12-52651585-G-T

Variant names:

• chr12-52651585-G-T
• rs137852632
• NM_000423.3:c.558C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000423.3(KRT2):​c.558C>A​(p.Asn186Lys) variant causes a missense change. 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. N186D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT2 NM_000423.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 4.73
• Publications: 3 publications found

Genes affected

KRT2 (HGNC:6439): (keratin 2) 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 expressed largely in the upper spinous layer of epidermal keratinocytes and mutations in this gene have been associated with bullous congenital ichthyosiform erythroderma. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

KRT2 Gene-Disease associations (from GenCC):

• superficial epidermolytic ichthyosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000423.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-52651587-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 9315.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 12-52651585-G-T is Pathogenic according to our data. Variant chr12-52651585-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9316.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT2	NM_000423.3	c.558C>A	p.Asn186Lys	missense_variant	Exon 1 of 9	ENST00000309680.4	NP_000414.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT2	ENST00000309680.4	c.558C>A	p.Asn186Lys	missense_variant	Exon 1 of 9	1	NM_000423.3	ENSP00000310861.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 18, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Located in the helix initiation motif that is intolerant of change; keratin gene 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11531804, 25979451, 26581228) -

Ichthyosis bullosa of Siemens Pathogenic:1

Aug 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		4.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.83		Gain of methylation at N186 (P = 0.0314);
MVP		0.97
MPC		0.50
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.85
gMVP		0.98
Mutation Taster		=29/71	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -27

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

Other links and lift over

dbSNP: rs137852632; hg19: chr12-53045369;