17-40819077-G-GCCGCCGCCGGAGCTTCCGCCGCCGGAGCTT

Position:

• chr17-40819077-G-GCCGCCGCCGGAGCTTCCGCCGCCGGAGCTT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM4 BP6_Moderate

The NM_000421.5(KRT10):​c.1457_1458insAAGCTCCGGCGGCGGAAGCTCCGGCGGCGG​(p.Ser477_Gly486dup) variant causes a inframe insertion 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 benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRT10 NM_000421.5 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.66

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000421.5.
• BP6: Variant 17-40819077-G-GCCGCCGCCGGAGCTTCCGCCGCCGGAGCTT is Benign according to our data. Variant chr17-40819077-G-GCCGCCGCCGGAGCTTCCGCCGCCGGAGCTT is described in ClinVar as [Likely_benign]. Clinvar id is 509767.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT10	NM_000421.5	c.1457_1458insAAGCTCCGGCGGCGGAAGCTCCGGCGGCGG	p.Ser477_Gly486dup	inframe_insertion	7/8	ENST00000269576.6	NP_000412.4
KRT10	NM_001379366.1	c.1457_1458insAAGCTCCGGCGGCGGAAGCTCCGGCGGCGG	p.Ser477_Gly486dup	inframe_insertion	7/8		NP_001366295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT10	ENST00000269576.6	c.1457_1458insAAGCTCCGGCGGCGGAAGCTCCGGCGGCGG	p.Ser477_Gly486dup	inframe_insertion	7/8	1	NM_000421.5	ENSP00000269576	P2
KRT10-AS1	ENST00000301665.9			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 18, 2017

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: rs753095095; hg19: chr17-38975329;