17-41610359-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_005557.4(KRT16):c.1252C>T(p.Arg418Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 1,612,720 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R418P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0062 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (91 hom.)
• Consequence: KRT16 NM_005557.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.58

Genes affected

KRT16 (HGNC:6423): (keratin 16) 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 and are clustered in a region of chromosome 17q12-q21. This keratin has been coexpressed with keratin 14 in a number of epithelial tissues, including esophagus, tongue, and hair follicles. Mutations in this gene are associated with type 1 pachyonychia congenita, non-epidermolytic palmoplantar keratoderma and unilateral palmoplantar verrucous nevus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-41610358-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.010027766).
• BP6: Variant 17-41610359-G-A is Benign according to our data. Variant chr17-41610359-G-A is described in ClinVar as [Benign]. Clinvar id is 788153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT16	NM_005557.4	c.1252C>T	p.Arg418Cys	missense_variant	6/8	ENST00000301653.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT16	ENST00000301653.9	c.1252C>T	p.Arg418Cys	missense_variant	6/8	1	NM_005557.4	P1
KRT16	ENST00000593067.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00616 AC: 938 AN: 152226 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.0551

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00586

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00965 AC: 2422 AN: 250988 Hom.: 48 AF XY: 0.00951 AC XY: 1291 AN XY: 135716

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.0640

Gnomad SAS exome AF: 0.0128

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00546

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00728 AC: 10627 AN: 1460376 Hom.: 91 Cov.: 35 AF XY: 0.00749 AC XY: 5439 AN XY: 726492

Gnomad4 AFR exome AF: 0.000897

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00700

Gnomad4 EAS exome AF: 0.0471

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.00273

Gnomad4 NFE exome AF: 0.00609

Gnomad4 OTH exome AF: 0.00881

GnomAD4 genome AF: 0.00616 AC: 939 AN: 152344 Hom.: 13 Cov.: 32 AF XY: 0.00670 AC XY: 499 AN XY: 74492

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.0554

Gnomad4 SAS AF: 0.0189

Gnomad4 FIN AF: 0.00282

Gnomad4 NFE AF: 0.00586

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00526 Hom.: 1

Bravo AF: 0.00577

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00977 AC: 1186

Asia WGS AF: 0.0340 AC: 118 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KRT16-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.75
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Polyphen		0.76	P
Vest4		0.50
MVP		0.87
MPC		0.77
ClinPred		0.097	T
GERP RS		1.9
Varity_R		0.31
gMVP		0.53

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: rs56259134; hg19: chr17-39766611; COSMIC: COSV56969139; COSMIC: COSV56969139;