chr17-40819075-T-TAGCCGCCGCCGCC

Variant names:

• chr17-40819075-T-TAGCCGCCGCCGCC
• rs764791942
• NM_000421.5:c.1459_1460insGGCGGCGGCGGCT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_000421.5(KRT10):​c.1459_1460insGGCGGCGGCGGCT​(p.His487ArgfsTer98) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 106,738 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, 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. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000094 (0 hom., cov: 24)
• Consequence: KRT10 NM_000421.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.352
• Publications: 3 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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.1459_1460insGGCGGCGGCGGCT	p.His487ArgfsTer98	frameshift	Exon 7 of 8	NP_000412.4
	KRT10	NM_001379366.1		c.1459_1460insGGCGGCGGCGGCT	p.His487ArgfsTer98	frameshift	Exon 7 of 8	NP_001366295.1	A0A1B0GVI3
	KRT10-AS1	NR_160886.1		n.-110_-109insAGCCGCCGCCGCC		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT10	ENST00000269576.6	TSL:1 MANE Select	c.1459_1460insGGCGGCGGCGGCT	p.His487ArgfsTer98	frameshift	Exon 7 of 8	ENSP00000269576.5	P13645
	KRT10	ENST00000635956.2	TSL:2	c.1459_1460insGGCGGCGGCGGCT	p.His487ArgfsTer98	frameshift	Exon 7 of 8	ENSP00000490524.2	A0A1B0GVI3
	KRT10-AS1	ENST00000436612.7	TSL:2	n.5_6insAGCCGCCGCCGCC		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00000937 AC: 1 AN: 106738 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 109

GnomAD4 genome AF: 0.00000937 AC: 1 AN: 106738 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 52036

African (AFR) AF: 0.0000312 AC: 1 AN: 32008

American (AMR) AF: 0.00 AC: 0 AN: 11118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2330

East Asian (EAS) AF: 0.00 AC: 0 AN: 2932

South Asian (SAS) AF: 0.00 AC: 0 AN: 2928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 162

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 47250

Other (OTH) AF: 0.00 AC: 0 AN: 1424

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.35
Mutation Taster		=91/109	disease causing

Splicing

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

Other links and lift over

dbSNP: rs764791942; hg19: chr17-38975327;