rs142750223

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005557.4(KRT16):c.539C>T(p.Ala180Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,609,484 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 19 hom. )

Consequence

KRT16
NM_005557.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.566

Publications

5 publications found

Variant links:

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]

KRT16 Gene-Disease associations (from GenCC):

pachyonychia congenita 1
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
palmoplantar keratoderma, nonepidermolytic, focal 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
isolated focal non-epidermolytic palmoplantar keratoderma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pachyonychia congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRT16 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008734137).

BP6

Variant 17-41611714-G-A is Benign according to our data. Variant chr17-41611714-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 587419.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00131 (200/152324) while in subpopulation SAS AF = 0.00787 (38/4830). AF 95% confidence interval is 0.00589. There are 0 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 200 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005557.4. 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
	KRT16	NM_005557.4	MANE Select	c.539C>T	p.Ala180Val	missense	Exon 2 of 8	NP_005548.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT16	ENST00000301653.9	TSL:1 MANE Select	c.539C>T	p.Ala180Val	missense	Exon 2 of 8	ENSP00000301653.3	P08779
KRT16	ENST00000593067.1	TSL:3	c.-176C>T		5_prime_UTR	Exon 3 of 7	ENSP00000467124.1	K7ENW6
KRT16	ENST00000588319.1	TSL:6	n.*52C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00132

AC:

201

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00786

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00241

AC:

579

AN:

240480

AF XY:

0.00287

show subpopulations

Gnomad AFR exome

AF:

0.000199

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.0140

Gnomad EAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.00404

GnomAD4 exome

AF:

0.00157

AC:

2289

AN:

1457160

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1328

AN XY:

724646

show subpopulations

African (AFR)

AF:

0.000420

AC:

AN:

33370

American (AMR)

AF:

0.00147

AC:

AN:

44330

Ashkenazi Jewish (ASJ)

AF:

0.0142

AC:

370

AN:

26052

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39642

South Asian (SAS)

AF:

0.00878

AC:

751

AN:

85504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00895

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.000784

AC:

871

AN:

1110750

Other (OTH)

AF:

0.00298

AC:

179

AN:

60134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

141

281

422

562

703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00131

AC:

200

AN:

152324

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41576

American (AMR)

AF:

0.00281

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00787

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68024

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00201

Hom.:

Bravo

AF:

0.00163

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00175

AC:

ExAC

AF:

0.00217

AC:

264

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Pachyonychia congenita 1 (1)

Palmoplantar keratoderma, epidermolytic (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.51

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.38

M_CAP

Benign

0.069

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.7

PhyloP100

-0.57

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.1

REVEL

Benign

0.20

Sift

Benign

0.18

Sift4G

Benign

0.27

Polyphen

0.094

Vest4

0.20

MVP

0.37

MPC

0.32

ClinPred

0.0060

GERP RS

-7.8

Varity_R

0.068

gMVP

0.40

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over