chr17-41582500-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000526.5(KRT14):c.1354G>A(p.Val452Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,572,222 control chromosomes in the GnomAD database, including 383 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 29 hom., cov: 32)

Exomes 𝑓: 0.020 ( 354 hom. )

Consequence

KRT14
NM_000526.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.710

Publications

7 publications found

Variant links:

COSMIC-nc: COSV107242418

Genes affected

KRT14 (HGNC:6416): (keratin 14) This gene encodes a member of the keratin family, the most diverse group of intermediate filaments. This gene product, a type I keratin, is usually found as a heterotetramer with two keratin 5 molecules, a type II keratin. Together they form the cytoskeleton of epithelial cells. Mutations in the genes for these keratins are associated with epidermolysis bullosa simplex. At least one pseudogene has been identified at 17p12-p11. [provided by RefSeq, Jul 2008]

KRT14 Gene-Disease associations (from GenCC):

epidermolysis bullosa simplex 1A, generalized severe
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet
Naegeli-Franceschetti-Jadassohn syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet, Genomics England PanelApp
epidermolysis bullosa simplex
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet
dermatopathia pigmentosa reticularis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
epidermolysis bullosa simplex 1B, generalized intermediate
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
epidermolysis bullosa simplex 1C, localized
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
epidermolysis bullosa simplex 2F, with mottled pigmentation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRT14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.8353 (below the threshold of 3.09). Trascript score misZ: 1.2925 (below the threshold of 3.09). GenCC associations: The gene is linked to epidermolysis bullosa simplex 2F, with mottled pigmentation, epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive, epidermolysis bullosa simplex 1A, generalized severe, epidermolysis bullosa simplex 1B, generalized intermediate, epidermolysis bullosa simplex 1C, localized, Naegeli-Franceschetti-Jadassohn syndrome, epidermolysis bullosa simplex, dermatopathia pigmentosa reticularis.

BP4

Computational evidence support a benign effect (MetaRNN=0.002311796).

BP6

Variant 17-41582500-C-T is Benign according to our data. Variant chr17-41582500-C-T is described in ClinVar as Benign. ClinVar VariationId is 1537948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0168 (2552/152262) while in subpopulation NFE AF = 0.0232 (1576/68020). AF 95% confidence interval is 0.0222. There are 29 homozygotes in GnomAd4. There are 1319 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000526.5. 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
	KRT14	NM_000526.5	MANE Select	c.1354G>A	p.Val452Ile	missense	Exon 8 of 8	NP_000517.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT14	ENST00000167586.7	TSL:1 MANE Select	c.1354G>A	p.Val452Ile	missense	Exon 8 of 8	ENSP00000167586.6	P02533
	KRT14	ENST00000441550.2	TSL:2	n.862G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2553

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00372

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0496

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.0164

AC:

3033

AN:

184884

AF XY:

0.0158

show subpopulations

Gnomad AFR exome

AF:

0.00402

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0463

Gnomad NFE exome

AF:

0.0221

Gnomad OTH exome

AF:

0.0167

GnomAD4 exome

AF:

0.0203

AC:

28842

AN:

1419960

Hom.:

354

Cov.:

AF XY:

0.0197

AC XY:

13841

AN XY:

702314

show subpopulations

African (AFR)

AF:

0.00308

AC:

100

AN:

32506

American (AMR)

AF:

0.0122

AC:

467

AN:

38342

Ashkenazi Jewish (ASJ)

AF:

0.00434

AC:

110

AN:

25350

East Asian (EAS)

AF:

0.0000802

AC:

AN:

37426

South Asian (SAS)

AF:

0.00207

AC:

167

AN:

80494

European-Finnish (FIN)

AF:

0.0458

AC:

2326

AN:

50732

Middle Eastern (MID)

AF:

0.00384

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0227

AC:

24730

AN:

1090438

Other (OTH)

AF:

0.0156

AC:

917

AN:

58950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

1387

2774

4162

5549

6936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

920

1840

2760

3680

4600

<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:

0.0168

AC:

2552

AN:

152262

Hom.:

Cov.:

AF XY:

0.0177

AC XY:

1319

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00371

AC:

154

AN:

41550

American (AMR)

AF:

0.0154

AC:

235

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0496

AC:

526

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0232

AC:

1576

AN:

68020

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

135

270

406

541

676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0159

Hom.:

Bravo

AF:

0.0138

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00568

AC:

ESP6500EA

AF:

0.0221

AC:

190

ExAC

AF:

0.0113

AC:

1343

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

Eigen

Benign

0.083

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.7

PhyloP100

0.71

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.30

REVEL

Benign

0.28

Sift

Benign

0.13

Sift4G

Benign

0.16

Polyphen

0.10

Vest4

0.063

MPC

0.54

ClinPred

0.053

GERP RS

5.4

Varity_R

0.098

gMVP

0.93

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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