17-41501281-C-T

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.1352G>A(p.Arg451His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,569,832 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (4 hom.)
• Consequence: KRT13 NM_153490.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.40

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=0.008725375).
• BP6: Variant 17-41501281-C-T is Benign according to our data. Variant chr17-41501281-C-T is described in ClinVar as [Benign]. Clinvar id is 323074.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT13	NM_153490.3	c.1352G>A	p.Arg451His	missense_variant	8/8	ENST00000246635.8
KRT13	NM_002274.4	c.*63G>A		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT13	ENST00000246635.8	c.1352G>A	p.Arg451His	missense_variant	8/8	1	NM_153490.3	P2
	ENST00000411759.1	n.299C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000326 AC: 60 AN: 184110 Hom.: 0 AF XY: 0.000482 AC XY: 47 AN XY: 97412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000762

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000256

Gnomad OTH exome AF: 0.000407

GnomAD4 exome AF: 0.000169 AC: 240 AN: 1417658 Hom.: 4 Cov.: 31 AF XY: 0.000250 AC XY: 175 AN XY: 700684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000540

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000827

Gnomad4 OTH exome AF: 0.000170

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74398

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000270 AC: 32

Asia WGS AF: 0.000289 AC: 1 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	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.27
Sift	Benign	0.058	T
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.34
MutPred		0.29		Loss of stability (P = 0.0617);
MVP		0.85
MPC		0.12
ClinPred		0.043	T
GERP RS		2.3
Varity_R		0.063
gMVP		0.069

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs550693344; hg19: chr17-39657533; COSMIC: COSV105852164; COSMIC: COSV105852164;