12-52675340-GCCGCCGCC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_006121.4(KRT1):c.1780_1787del(p.Gly594ArgfsTer57) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G594G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT1 NM_006121.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.03

Genes affected

KRT1 (HGNC:6412): (keratin 1) 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 spinous and granular layers of the epidermis with family member KRT10 and mutations in these genes 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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 0.0801 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-52675340-GCCGCCGCC-G is Pathogenic according to our data. Variant chr12-52675340-GCCGCCGCC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817768.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT1	NM_006121.4	c.1780_1787del	p.Gly594ArgfsTer57	frameshift_variant	9/9	ENST00000252244.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT1	ENST00000252244.3	c.1780_1787del	p.Gly594ArgfsTer57	frameshift_variant	9/9	1	NM_006121.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2018

The c.1780_1787delGGCGGCGG variant in the KRT1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016). It causes a frameshift starting with codon Glycine 594, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 57 of the new reading frame, denoted p.Gly594ArgfsX57. This variant replaces the final 51 amino acids with 56 incorrect amino acids. We consider this variant to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1592264179; hg19: chr12-53069124;