17-41501357-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_153490.3(KRT13):c.1276G>A(p.Val426Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,559,626 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: KRT13 NM_153490.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.67

Genes affected

KRT13 (HGNC:6415): (keratin 13) The protein encoded by this gene is a member of the keratin gene family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. Most of the type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. This type I cytokeratin is paired with keratin 4 and expressed in the suprabasal layers of non-cornified stratified epithelia. Mutations in this gene and keratin 4 have been associated with the autosomal dominant disorder White Sponge Nevus. The type I cytokeratins are clustered in a region of chromosome 17q21.2. Alternative splicing of this gene results in multiple transcript variants; however, not all variants have been described. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053011775).
• BP6: Variant 17-41501357-C-T is Benign according to our data. Variant chr17-41501357-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 323076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 223 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT13	NM_153490.3	c.1276G>A	p.Val426Ile	missense_variant	8/8	ENST00000246635.8
KRT13	NM_002274.4	c.1250G>A	p.Arg417His	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT13	ENST00000246635.8	c.1276G>A	p.Val426Ile	missense_variant	8/8	1	NM_153490.3	P2
	ENST00000411759.1	n.334+41C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152136 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00107 AC: 179 AN: 167754 Hom.: 1 AF XY: 0.00114 AC XY: 101 AN XY: 88276

Gnomad AFR exome AF: 0.000198

Gnomad AMR exome AF: 0.000200

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.0000782

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00140

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.000863

GnomAD4 exome AF: 0.00129 AC: 1809 AN: 1407372 Hom.: 5 Cov.: 30 AF XY: 0.00133 AC XY: 927 AN XY: 694828

Gnomad4 AFR exome AF: 0.000246

Gnomad4 AMR exome AF: 0.000333

Gnomad4 ASJ exome AF: 0.000913

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00219

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.000959

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152254 Hom.: 2 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74440

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00189 Hom.: 1

Bravo AF: 0.00104

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.000728 AC: 81

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KRT13-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2020

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). -

White sponge nevus 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.042
Dann	Benign	0.74
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.17
Sift	Benign	0.039	D
Sift4G	Benign	0.11	T
Polyphen		0.45	B
Vest4		0.023
MVP		0.33
ClinPred		0.019	T
GERP RS		-1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs144967807; hg19: chr17-39657609;