Genetic Variant KRT10:p.Gly556_Tyr557insSerSerSerGlyGlyGly (chr17-40818867-T-TCCGCCGCCGGAGCTGCTG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_000421.5(KRT10):c.1650_1667dupCAGCAGCTCCGGCGGCGG(p.Gly556_Tyr557insSerSerSerGlyGlyGly) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,535,770 control chromosomes in the GnomAD database, including 1 homozygotes. 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000055 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

KRT10
NM_000421.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.33

Publications

0 publications found

Variant links:

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 links:

KRT10-AS1 (HGNC:28305): (KRT10 antisense RNA 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

KRT10-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000421.5.

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.1650_1667dupCAGCAGCTCCGGCGGCGG	p.Gly556_Tyr557insSerSerSerGlyGlyGly	disruptive_inframe_insertion	Exon 7 of 8	NP_000412.4
	KRT10	NM_001379366.1		c.1650_1667dupCAGCAGCTCCGGCGGCGG	p.Gly556_Tyr557insSerSerSerGlyGlyGly	disruptive_inframe_insertion	Exon 7 of 8	NP_001366295.1	A0A1B0GVI3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT10	ENST00000269576.6	TSL:1 MANE Select	c.1650_1667dupCAGCAGCTCCGGCGGCGG	p.Gly556_Tyr557insSerSerSerGlyGlyGly	disruptive_inframe_insertion	Exon 7 of 8	ENSP00000269576.5	P13645
KRT10	ENST00000635956.2	TSL:2	c.1650_1667dupCAGCAGCTCCGGCGGCGG	p.Gly556_Tyr557insSerSerSerGlyGlyGly	disruptive_inframe_insertion	Exon 7 of 8	ENSP00000490524.2	A0A1B0GVI3
KRT10-AS1	ENST00000301665.10	TSL:2	n.-231_-230insCCGCCGCCGGAGCTGCTG		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000552

AC:

AN:

145010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000680

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00355

Gnomad NFE

AF:

0.0000613

Gnomad OTH

AF:

0.000502

GnomAD2 exomes

AF:

0.0000522

AC:

AN:

191424

AF XY:

0.0000554

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000360

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000864

Gnomad OTH exome

AF:

0.000219

GnomAD4 exome

AF:

0.0000395

AC:

AN:

1390646

Hom.:

Cov.:

AF XY:

0.0000376

AC XY:

AN XY:

692386

show subpopulations

African (AFR)

AF:

0.0000336

AC:

AN:

29758

American (AMR)

AF:

0.0000993

AC:

AN:

40284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24610

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35536

South Asian (SAS)

AF:

0.0000250

AC:

AN:

79850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35974

Middle Eastern (MID)

AF:

0.000536

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

0.0000361

AC:

AN:

1081618

Other (OTH)

AF:

0.0000871

AC:

AN:

57414

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000551

AC:

AN:

145124

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

70886

show subpopulations

African (AFR)

AF:

0.0000253

AC:

AN:

39488

American (AMR)

AF:

0.0000679

AC:

AN:

14734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3350

East Asian (EAS)

AF:

0.00

AC:

AN:

4932

South Asian (SAS)

AF:

0.00

AC:

AN:

4510

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9708

Middle Eastern (MID)

AF:

0.00379

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.0000613

AC:

AN:

65256

Other (OTH)

AF:

0.000496

AC:

AN:

2018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000435

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ichthyosis hystrix gravior;C3665704:Congenital reticular ichthyosiform erythroderma;C5882671:Epidermolytic hyperkeratosis 2A, autosomal dominant;C5882753:Epidermolytic hyperkeratosis 2B, autosomal recessive;CN324065:Ichthyosis, annular epidermolytic 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Mutation Taster

=90/10

polymorphism

(source)

Splicing

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

Publications

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17-40818867-TCCGCCGCCGGAGCTGCTG-TCCGCCGCCGGAGCTGCTGCCGCCGCCGGAGCTGCTG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over