17-40822106-GT-CG

Variant names:

• chr17-40822106-GT-CG
• NM_000421.5:c.479_480delACinsCG
• KRT10 p.Tyr160Ser

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM5 PP3

The NM_000421.5(KRT10):​c.479_480delACinsCG​(p.Tyr160Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y160D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT10 NM_000421.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.00
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000421.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-40822108-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14572.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000421.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT10	NM_000421.5	MANE Select	c.479_480delACinsCG	p.Tyr160Ser	missense	N/A	NP_000412.4
	KRT10	NM_001379366.1		c.479_480delACinsCG	p.Tyr160Ser	missense	N/A	NP_001366295.1	A0A1B0GVI3
	KRT10-AS1	NR_160886.1		n.95+2827_95+2828delGTinsCG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT10	ENST00000269576.6	TSL:1 MANE Select	c.479_480delACinsCG	p.Tyr160Ser	missense	N/A	ENSP00000269576.5	P13645
	KRT10	ENST00000635956.2	TSL:2	c.479_480delACinsCG	p.Tyr160Ser	missense	N/A	ENSP00000490524.2	A0A1B0GVI3
	KRT10-AS1	ENST00000301665.10	TSL:2	n.111+2898_111+2899delGTinsCG		intron	N/A

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-38978358;