12-52675230-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006121.4(KRT1):c.1898A>G(p.Lys633Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,660 control chromosomes in the GnomAD database, including 80,446 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 0.24 ( 5697 hom., cov: 32)

Exomes 𝑓: 0.31 ( 74749 hom. )

Consequence

KRT1
NM_006121.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.673

Publications

40 publications found

Variant links:

Genes affected

KRT1 (HGNC:6412): (keratin 1) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the spinous and granular layers of the epidermis with family member KRT10 and mutations in these genes have been associated with bullous congenital ichthyosiform erythroderma. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

KRT1 Gene-Disease associations (from GenCC):

annular epidermolytic ichthyosis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, PanelApp Australia
ichthyosis hystrix of Curth-Macklin
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, PanelApp Australia
diffuse nonepidermolytic palmoplantar keratoderma
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
epidermolytic ichthyosis
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Orphanet, Genomics England PanelApp, PanelApp Australia
ichthyosis, annular epidermolytic 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
ichthyosis, annular epidermolytic, 2
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
congenital reticular ichthyosiform erythroderma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
striate palmoplantar keratoderma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive congenital ichthyosis 11
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

KRT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.6852023E-5).

BP6

Variant 12-52675230-T-C is Benign according to our data. Variant chr12-52675230-T-C is described in ClinVar as Benign. ClinVar VariationId is 309637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT1	NM_006121.4 link	c.1898A>G	p.Lys633Arg	missense_variant	Exon 9 of 9	ENST00000252244.3	NP_006112.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT1	ENST00000252244.3 link	c.1898A>G	p.Lys633Arg	missense_variant	Exon 9 of 9	1	NM_006121.4	ENSP00000252244.3

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37248

AN:

151990

Hom.:

5701

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0643

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.312

Gnomad EAS

AF:

0.577

Gnomad SAS

AF:

0.273

Gnomad FIN

AF:

0.350

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.309

Gnomad OTH

AF:

0.255

GnomAD2 exomes

AF:

0.309

AC:

77483

AN:

250558

AF XY:

0.310

show subpopulations

Gnomad AFR exome

AF:

0.0591

Gnomad AMR exome

AF:

0.285

Gnomad ASJ exome

AF:

0.313

Gnomad EAS exome

AF:

0.590

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.309

Gnomad OTH exome

AF:

0.321

GnomAD4 exome

AF:

0.312

AC:

456341

AN:

1461552

Hom.:

74749

Cov.:

AF XY:

0.312

AC XY:

226538

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.0534

AC:

1787

AN:

33468

American (AMR)

AF:

0.279

AC:

12459

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

8058

AN:

26136

East Asian (EAS)

AF:

0.595

AC:

23630

AN:

39696

South Asian (SAS)

AF:

0.272

AC:

23465

AN:

86242

European-Finnish (FIN)

AF:

0.345

AC:

18423

AN:

53386

Middle Eastern (MID)

AF:

0.291

AC:

1610

AN:

5542

European-Non Finnish (NFE)

AF:

0.313

AC:

348003

AN:

1111992

Other (OTH)

AF:

0.313

AC:

18906

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

21618

43236

64853

86471

108089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11400

22800

34200

45600

57000

<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:

0.245

AC:

37227

AN:

152108

Hom.:

5697

Cov.:

AF XY:

0.248

AC XY:

18415

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0641

AC:

2661

AN:

41538

American (AMR)

AF:

0.245

AC:

3742

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

1083

AN:

3470

East Asian (EAS)

AF:

0.577

AC:

2975

AN:

5154

South Asian (SAS)

AF:

0.272

AC:

1308

AN:

4814

European-Finnish (FIN)

AF:

0.350

AC:

3705

AN:

10576

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.309

AC:

21023

AN:

67938

Other (OTH)

AF:

0.252

AC:

532

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1368

2736

4103

5471

6839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.286

Hom.:

20356

Bravo

AF:

0.233

TwinsUK

AF:

0.304

AC:

1126

ALSPAC

AF:

0.300

AC:

1157

ESP6500AA

AF:

0.0681

AC:

300

ESP6500EA

AF:

0.303

AC:

2605

ExAC

AF:

0.304

AC:

36879

Asia WGS

AF:

0.360

AC:

1252

AN:

3478

EpiCase

AF:

0.302

EpiControl

AF:

0.298

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epidermolytic ichthyosis

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diffuse nonepidermolytic palmoplantar keratoderma

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.074

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.45

MetaRNN

Benign

0.000057

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.3

PhyloP100

0.67

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.59

REVEL

Benign

0.14

Sift

Pathogenic

0.0

Sift4G

Benign

0.92

Polyphen

0.33

Vest4

0.064

MPC

0.22

ClinPred

0.026

GERP RS

2.3

Varity_R

0.21

gMVP

0.59

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over