17-40818851-A-AGCTGCCGCCGCCGTATCCGCCGCCGGAGCTGCTGCCGCCGCCGTATCCGCCGCCGGAGCT

Position:

• chr17-40818851-A-AGCTGCCGCCGCCGTATCCGCCGCCGGAGCTGCTGCCGCCGCCGTATCCGCCGCCGGAGCT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

The NM_000421.5(KRT10):​c.1683_1684insAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGC​(p.Gly565_His566insGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGly) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (209 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (460 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT10 NM_000421.5 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0440

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000421.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT10	NM_000421.5	c.1683_1684insAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGC	p.Gly565_His566insGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGly	inframe_insertion	7/8	ENST00000269576.6	NP_000412.4
KRT10	NM_001379366.1	c.1683_1684insAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGC	p.Gly565_His566insGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGly	inframe_insertion	7/8		NP_001366295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT10	ENST00000269576.6	c.1683_1684insAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGC	p.Gly565_His566insGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGly	inframe_insertion	7/8	1	NM_000421.5	ENSP00000269576	P2
KRT10	ENST00000635956.2	c.1683_1684insAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGC	p.Gly565_His566insGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGly	inframe_insertion	7/8	2		ENSP00000490524	A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2640 AN: 130536 Hom.: 210 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.0223

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0316

Gnomad EAS AF: 0.0856

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.0257

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0278

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00791 AC: 10080 AN: 1273676 Hom.: 460 Cov.: 31 AF XY: 0.00818 AC XY: 5184 AN XY: 633478

Gnomad4 AFR exome AF: 0.00864

Gnomad4 AMR exome AF: 0.00495

Gnomad4 ASJ exome AF: 0.0219

Gnomad4 EAS exome AF: 0.0568

Gnomad4 SAS exome AF: 0.00605

Gnomad4 FIN exome AF: 0.0234

Gnomad4 NFE exome AF: 0.00535

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0202 AC: 2639 AN: 130638 Hom.: 209 Cov.: 33 AF XY: 0.0198 AC XY: 1260 AN XY: 63564

Gnomad4 AFR AF: 0.0172

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0316

Gnomad4 EAS AF: 0.0859

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0269

Alfa AF: 0.000791 Hom.: 65

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KRT10 p.Gly565_His566ins20 variant was not identified in the literature nor was it identified in dbSNP, ClinVar, LOVD 3.0 or the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame insertion resulting in the insertion of 20 amino acids beginning at codon 565; the impact of this alteration on KRT10 protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with KRT10-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.1683_1684ins60, results in the insertion of 20 amino acid(s) of the KRT10 protein (p.Gly565_His566ins20), but otherwise preserves the integrity of the reading frame. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 28, 2022

- -

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: rs776920005; hg19: chr17-38975103;