17-40818851-A-AGCTGCCGCCGCCGTATCCGCCGCCGGAGCTGCTGCCGCCGCCGTATCCGCCGCCGGAGCTGCTGCCGCCGCCGTATCCGCCGCCGGAGCT

Position:

• chr17-40818851-A-AGCTGCCGCCGCCGTATCCGCCGCCGGAGCTGCTGCCGCCGCCGTATCCGCCGCCGGAGCTGCTGCCGCCGCCGTATCCGCCGCCGGAGCT

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BP6 BS2

The NM_000421.5(KRT10):​c.1683_1684insAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGC​(p.Ser561_Ser562insSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySer) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000669 in 1,405,870 control chromosomes in the GnomAD database, including 60 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (23 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (37 hom.)
• Consequence: KRT10 NM_000421.5 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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 Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000421.5.
• BP6: Variant 17-40818851-A-AGCTGCCGCCGCCGTATCCGCCGCCGGAGCTGCTGCCGCCGCCGTATCCGCCGCCGGAGCTGCTGCCGCCGCCGTATCCGCCGCCGGAGCT is Benign according to our data. Variant chr17-40818851-A-AGCTGCCGCCGCCGTATCCGCCGCCGGAGCTGCTGCCGCCGCCGTATCCGCCGCCGGAGCTGCTGCCGCCGCCGTATCCGCCGCCGGAGCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420788.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Homozygotes in GnomAd4 at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT10	NM_000421.5	c.1683_1684insAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGC	p.Ser561_Ser562insSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySer	inframe_insertion	7/8	ENST00000269576.6
KRT10	NM_001379366.1	c.1683_1684insAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGC	p.Gly565_His566insGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGly	inframe_insertion	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT10	ENST00000269576.6	c.1683_1684insAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGC	p.Ser561_Ser562insSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySer	inframe_insertion	7/8	1	NM_000421.5	P2
KRT10	ENST00000635956.2	c.1683_1684insAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGCAGCTCCGGCGGCGGATACGGCGGCGGCAGC	p.Gly565_His566insGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGlyGlyTyrGlyGlyGlySerSerSerGlyGly	inframe_insertion	7/8	2		A2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 190 AN: 130754 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00101

Gnomad FIN AF: 0.00101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000894

Gnomad OTH AF: 0.000567

GnomAD4 exome AF: 0.000588 AC: 750 AN: 1275014 Hom.: 37 Cov.: 31 AF XY: 0.000593 AC XY: 376 AN XY: 634240

Gnomad4 AFR exome AF: 0.00303

Gnomad4 AMR exome AF: 0.000412

Gnomad4 ASJ exome AF: 0.0000862

Gnomad4 EAS exome AF: 0.000604

Gnomad4 SAS exome AF: 0.000762

Gnomad4 FIN exome AF: 0.00330

Gnomad4 NFE exome AF: 0.000409

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00146 AC: 191 AN: 130856 Hom.: 23 Cov.: 33 AF XY: 0.00144 AC XY: 92 AN XY: 63692

Gnomad4 AFR AF: 0.00332

Gnomad4 AMR AF: 0.00101

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00101

Gnomad4 FIN AF: 0.00101

Gnomad4 NFE AF: 0.000894

Gnomad4 OTH AF: 0.000559

Alfa AF: 0.000119 Hom.: 65

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

This variant, c.1683_1684ins90, results in the insertion of 30 amino acid(s) of the KRT10 protein (p.Gly565_His566ins30), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KRT10-related conditions. ClinVar contains an entry for this variant (Variation ID: 420788). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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;