17-40818878-A-AGCT

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PM4_Supporting BP6_Very_Strong BS2

The NM_000421.5(KRT10):c.1656_1657insAGC(p.Ser553dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000504 in 1,530,434 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: KRT10 NM_000421.5 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.05

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 Benign. Variant got -11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000421.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 17-40818878-A-AGCT is Benign according to our data. Variant chr17-40818878-A-AGCT is described in ClinVar as [Likely_benign]. Clinvar id is 1541400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT10	NM_000421.5	c.1656_1657insAGC	p.Ser553dup	inframe_insertion	7/8	ENST00000269576.6
KRT10	NM_001379366.1	c.1656_1657insAGC	p.Ser553dup	inframe_insertion	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT10	ENST00000269576.6	c.1656_1657insAGC	p.Ser553dup	inframe_insertion	7/8	1	NM_000421.5	P2
KRT10	ENST00000635956.2	c.1656_1657insAGC	p.Ser553dup	inframe_insertion	7/8	2		A2

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 412 AN: 148342 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000733

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000451

Gnomad OTH AF: 0.00195

GnomAD3 exomes AF: 0.000465 AC: 86 AN: 185072 Hom.: 1 AF XY: 0.000333 AC XY: 35 AN XY: 105042

Gnomad AFR exome AF: 0.00873

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000225

Gnomad OTH exome AF: 0.000454

GnomAD4 exome AF: 0.000261 AC: 361 AN: 1381986 Hom.: 1 Cov.: 31 AF XY: 0.000206 AC XY: 142 AN XY: 687732

Gnomad4 AFR exome AF: 0.00958

Gnomad4 AMR exome AF: 0.000458

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.000807

GnomAD4 genome AF: 0.00277 AC: 411 AN: 148448 Hom.: 2 Cov.: 33 AF XY: 0.00280 AC XY: 203 AN XY: 72528

Gnomad4 AFR AF: 0.00971

Gnomad4 AMR AF: 0.000732

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000451

Gnomad4 OTH AF: 0.00193

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KRT10-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

- -

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: rs570343417; hg19: chr17-38975130;