rs142137272

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_000526.5(KRT14):c.202G>A(p.Gly68Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,608,828 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 14 hom. )

Consequence

KRT14
NM_000526.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.381

Publications

3 publications found

Variant links:

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: Orphanet, Ambry Genetics, Genomics England PanelApp
Naegeli-Franceschetti-Jadassohn syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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), Orphanet, Ambry Genetics, Genomics England PanelApp
dermatopathia pigmentosa reticularis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
epidermolysis bullosa simplex 1B, generalized intermediate
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
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 -15 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 1D, generalized, intermediate or severe, autosomal recessive, Naegeli-Franceschetti-Jadassohn syndrome, dermatopathia pigmentosa reticularis, epidermolysis bullosa simplex 1B, generalized intermediate, epidermolysis bullosa simplex 2F, with mottled pigmentation, epidermolysis bullosa simplex 1C, localized, epidermolysis bullosa simplex 1A, generalized severe, epidermolysis bullosa simplex.

BP4

Computational evidence support a benign effect (MetaRNN=0.008318633).

BP6

Variant 17-41586633-C-T is Benign according to our data. Variant chr17-41586633-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 14 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT14	NM_000526.5 link	c.202G>A	p.Gly68Ser	missense_variant	Exon 1 of 8	ENST00000167586.7	NP_000517.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT14	ENST00000167586.7 link	c.202G>A	p.Gly68Ser	missense_variant	Exon 1 of 8	1	NM_000526.5	ENSP00000167586.6

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

331

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00313

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00248

AC:

556

AN:

223748

AF XY:

0.00244

show subpopulations

Gnomad AFR exome

AF:

0.000506

Gnomad AMR exome

AF:

0.00366

Gnomad ASJ exome

AF:

0.00834

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000644

Gnomad NFE exome

AF:

0.00309

Gnomad OTH exome

AF:

0.00605

GnomAD4 exome

AF:

0.00301

AC:

4377

AN:

1456542

Hom.:

Cov.:

100

AF XY:

0.00290

AC XY:

2101

AN XY:

724406

show subpopulations

African (AFR)

AF:

0.000510

AC:

AN:

33338

American (AMR)

AF:

0.00358

AC:

156

AN:

43592

Ashkenazi Jewish (ASJ)

AF:

0.0102

AC:

265

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39400

South Asian (SAS)

AF:

0.000105

AC:

AN:

85958

European-Finnish (FIN)

AF:

0.000530

AC:

AN:

52834

Middle Eastern (MID)

AF:

0.000882

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00337

AC:

3736

AN:

1109596

Other (OTH)

AF:

0.00268

AC:

161

AN:

60110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

299

597

896

1194

1493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.00217

AC:

331

AN:

152286

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

156

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41566

American (AMR)

AF:

0.00340

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00313

AC:

213

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00343

Hom.:

Bravo

AF:

0.00253

ESP6500AA

AF:

0.000457

AC:

ESP6500EA

AF:

0.00281

AC:

ExAC

AF:

0.00209

AC:

251

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.20

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.38

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.0083

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.9

PhyloP100

0.38

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.2

REVEL

Benign

0.28

Sift

Benign

0.50

Sift4G

Benign

0.13

Polyphen

0.0030

Vest4

0.23

MVP

0.75

MPC

0.47

ClinPred

0.018

GERP RS

3.9

PromoterAI

0.027

Neutral

(source)

Varity_R

0.049

gMVP

0.83

Mutation Taster

=96/4

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over