17-40818881-T-TGCTGCCGCCGCCGGA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS2

The NM_000421.5(KRT10):c.1653_1654insTCCGGCGGCGGCAGC(p.Gly548_Ser552dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,525,934 control chromosomes in the GnomAD database, including 25 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (22 hom.)
• Consequence: KRT10 NM_000421.5 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.15

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 -10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000421.5.
• BP6: Variant 17-40818881-T-TGCTGCCGCCGCCGGA is Benign according to our data. Variant chr17-40818881-T-TGCTGCCGCCGCCGGA is described in ClinVar as [Likely_benign]. Clinvar id is 808260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT10	NM_000421.5	c.1653_1654insTCCGGCGGCGGCAGC	p.Gly548_Ser552dup	inframe_insertion	7/8	ENST00000269576.6
KRT10	NM_001379366.1	c.1653_1654insTCCGGCGGCGGCAGC	p.Gly548_Ser552dup	inframe_insertion	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT10	ENST00000269576.6	c.1653_1654insTCCGGCGGCGGCAGC	p.Gly548_Ser552dup	inframe_insertion	7/8	1	NM_000421.5	P2
KRT10	ENST00000635956.2	c.1653_1654insTCCGGCGGCGGCAGC	p.Gly548_Ser552dup	inframe_insertion	7/8	2		A2

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 486 AN: 148630 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000935

Gnomad ASJ AF: 0.00878

Gnomad EAS AF: 0.000393

Gnomad SAS AF: 0.00107

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00443

Gnomad OTH AF: 0.00441

GnomAD3 exomes AF: 0.00180 AC: 321 AN: 178706 Hom.: 2 AF XY: 0.00163 AC XY: 166 AN XY: 101592

Gnomad AFR exome AF: 0.000267

Gnomad AMR exome AF: 0.000569

Gnomad ASJ exome AF: 0.00451

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000202

Gnomad FIN exome AF: 0.00604

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00237

GnomAD4 exome AF: 0.00303 AC: 4172 AN: 1377196 Hom.: 22 Cov.: 31 AF XY: 0.00296 AC XY: 2028 AN XY: 685136

Gnomad4 AFR exome AF: 0.000242

Gnomad4 AMR exome AF: 0.000825

Gnomad4 ASJ exome AF: 0.00682

Gnomad4 EAS exome AF: 0.0000290

Gnomad4 SAS exome AF: 0.000281

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.00314

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.00327 AC: 486 AN: 148738 Hom.: 3 Cov.: 33 AF XY: 0.00355 AC XY: 258 AN XY: 72700

Gnomad4 AFR AF: 0.000371

Gnomad4 AMR AF: 0.000934

Gnomad4 ASJ AF: 0.00878

Gnomad4 EAS AF: 0.000394

Gnomad4 SAS AF: 0.00107

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.00443

Gnomad4 OTH AF: 0.00437

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	KRT10: BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	- -

KRT10-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2019

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

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: rs752563839; hg19: chr17-38975133;