17-41501267-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_153490.3(KRT13):c.1366C>T(p.Arg456Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,563,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: KRT13 NM_153490.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.46

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020168334).
• BP6: Variant 17-41501267-G-A is Benign according to our data. Variant chr17-41501267-G-A is described in ClinVar as [Benign]. Clinvar id is 889143.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT13	NM_153490.3	c.1366C>T	p.Arg456Cys	missense_variant	8/8	ENST00000246635.8
KRT13	NM_002274.4	c.*77C>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT13	ENST00000246635.8	c.1366C>T	p.Arg456Cys	missense_variant	8/8	1	NM_153490.3	P2
	ENST00000411759.1	n.285G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000425 AC: 75 AN: 176582 Hom.: 1 AF XY: 0.000418 AC XY: 39 AN XY: 93250

Gnomad AFR exome AF: 0.0000922

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000672

Gnomad FIN exome AF: 0.0000623

Gnomad NFE exome AF: 0.000766

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.000491 AC: 693 AN: 1411364 Hom.: 1 Cov.: 30 AF XY: 0.000483 AC XY: 337 AN XY: 697134

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000799

Gnomad4 FIN exome AF: 0.0000400

Gnomad4 NFE exome AF: 0.000561

Gnomad4 OTH exome AF: 0.000188

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74434

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000528 Hom.: 0

Bravo AF: 0.000351

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.000214 AC: 25

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

White sponge nevus 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.33
MVP		0.83
MPC		0.15
ClinPred		0.072	T
GERP RS		1.3
Varity_R		0.11
gMVP		0.077

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146666963; hg19: chr17-39657519; COSMIC: COSV55840367; COSMIC: COSV55840367;