chr17-40818878-A-AGCT

Variant names:

• chr17-40818878-A-AGCT
• rs570343417
• NM_000421.5:c.1654_1656dupAGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PM4_Supporting BP6_Moderate BS2

The NM_000421.5(KRT10):​c.1654_1656dupAGC​(p.Ser552dup) variant causes a conservative 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: KRT10 NM_000421.5 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.05
• 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: Likely_benign. The variant received -5 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 Benign. ClinVar VariationId is 1541400.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.1654_1656dupAGC	p.Ser552dup	conservative_inframe_insertion	Exon 7 of 8	NP_000412.4
	KRT10	NM_001379366.1		c.1654_1656dupAGC	p.Ser552dup	conservative_inframe_insertion	Exon 7 of 8	NP_001366295.1	A0A1B0GVI3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT10	ENST00000269576.6	TSL:1 MANE Select	c.1654_1656dupAGC	p.Ser552dup	conservative_inframe_insertion	Exon 7 of 8	ENSP00000269576.5	P13645
	KRT10	ENST00000635956.2	TSL:2	c.1654_1656dupAGC	p.Ser552dup	conservative_inframe_insertion	Exon 7 of 8	ENSP00000490524.2	A0A1B0GVI3
	KRT10-AS1	ENST00000301665.10	TSL:2	n.-220_-219insGCT		upstream_gene	N/A

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

GnomAD2 exomes AF: 0.000465 AC: 86 AN: 185072 AF XY: 0.000333

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 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

African (AFR) AF: 0.00958 AC: 279 AN: 29124

American (AMR) AF: 0.000458 AC: 18 AN: 39272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24362

East Asian (EAS) AF: 0.00 AC: 0 AN: 34754

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 78944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35586

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5558

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1077414

Other (OTH) AF: 0.000807 AC: 46 AN: 56972

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

African (AFR) AF: 0.00971 AC: 393 AN: 40474

American (AMR) AF: 0.000732 AC: 11 AN: 15028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5044

South Asian (SAS) AF: 0.00 AC: 0 AN: 4662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000451 AC: 3 AN: 66572

Other (OTH) AF: 0.00193 AC: 4 AN: 2074

Alfa AF: 0.0000614 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	KRT10-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
Mutation Taster		=88/12	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs570343417; hg19: chr17-38975130;