chr17-40819077-G-GAGCTT

Variant names:

• chr17-40819077-G-GAGCTT
• rs762667965
• NM_000421.5:c.1457_1458insAAGCT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 8P and 10B. PVS1 BP6_Moderate BA1

The NM_000421.5(KRT10):​c.1457_1458insAAGCT​(p.His487SerfsTer134) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 145,920 control chromosomes in the GnomAD database, including 131 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.022 (131 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (82 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT10 NM_000421.5 frameshift
• Clinical Significance: Benign criteria provided, single submitter U:2 B:1
• Conservation: PhyloP100: 2.66
• Publications: 1 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 -2 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 17-40819077-G-GAGCTT is Benign according to our data. Variant chr17-40819077-G-GAGCTT is described in ClinVar as Benign. ClinVar VariationId is 1175680.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0729 is higher than 0.05.

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.1457_1458insAAGCT	p.His487SerfsTer134	frameshift	Exon 7 of 8	NP_000412.4
	KRT10	NM_001379366.1		c.1457_1458insAAGCT	p.His487SerfsTer112	frameshift	Exon 7 of 8	NP_001366295.1	A0A1B0GVI3
	KRT10-AS1	NR_160886.1		n.-108_-107insAGCTT		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT10	ENST00000269576.6	TSL:1 MANE Select	c.1457_1458insAAGCT	p.His487SerfsTer134	frameshift	Exon 7 of 8	ENSP00000269576.5	P13645
	KRT10	ENST00000635956.2	TSL:2	c.1457_1458insAAGCT	p.His487SerfsTer112	frameshift	Exon 7 of 8	ENSP00000490524.2	A0A1B0GVI3
	KRT10-AS1	ENST00000436612.7	TSL:2	n.7_8insAGCTT		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3188 AN: 145822 Hom.: 132 Cov.: 31

Gnomad AFR AF: 0.0752

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00682

Gnomad ASJ AF: 0.00561

Gnomad EAS AF: 0.00389

Gnomad SAS AF: 0.000665

Gnomad FIN AF: 0.000604

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000848

Gnomad OTH AF: 0.0207

GnomAD2 exomes AF: 0.00235 AC: 167 AN: 70924 AF XY: 0.00214

Gnomad AFR exome AF: 0.0674

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00482

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000206

Gnomad NFE exome AF: 0.000845

Gnomad OTH exome AF: 0.00199

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00293 AC: 3689 AN: 1257990 Hom.: 82 Cov.: 34 AF XY: 0.00269 AC XY: 1667 AN XY: 619622

African (AFR) AF: 0.0786 AC: 1980 AN: 25204

American (AMR) AF: 0.00389 AC: 90 AN: 23144

Ashkenazi Jewish (ASJ) AF: 0.00550 AC: 121 AN: 22012

East Asian (EAS) AF: 0.000965 AC: 26 AN: 26944

South Asian (SAS) AF: 0.000793 AC: 53 AN: 66876

European-Finnish (FIN) AF: 0.000876 AC: 27 AN: 30820

Middle Eastern (MID) AF: 0.00252 AC: 10 AN: 3974

European-Non Finnish (NFE) AF: 0.00107 AC: 1078 AN: 1007366

Other (OTH) AF: 0.00589 AC: 304 AN: 51650

GnomAD4 genome AF: 0.0219 AC: 3196 AN: 145920 Hom.: 131 Cov.: 31 AF XY: 0.0209 AC XY: 1485 AN XY: 71206

African (AFR) AF: 0.0752 AC: 2953 AN: 39264

American (AMR) AF: 0.00682 AC: 101 AN: 14820

Ashkenazi Jewish (ASJ) AF: 0.00561 AC: 19 AN: 3388

East Asian (EAS) AF: 0.00349 AC: 17 AN: 4868

South Asian (SAS) AF: 0.000665 AC: 3 AN: 4508

European-Finnish (FIN) AF: 0.000604 AC: 6 AN: 9930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000848 AC: 56 AN: 66000

Other (OTH) AF: 0.0205 AC: 41 AN: 1998

Alfa AF: 0.000448 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=161/39	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs762667965; hg19: chr17-38975329;