12-52949441-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP3_ModerateBP6_Moderate

The NM_000224.3(KRT18):c.268C>T(p.Arg90Cys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.47 ( 0 hom., cov: 38)

Exomes 𝑓: 0.00039 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRT18
NM_000224.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 7.89

Variant links:

Genes affected

KRT18 (HGNC:6430): (keratin 18) KRT18 encodes the type I intermediate filament chain keratin 18. Keratin 18, together with its filament partner keratin 8, are perhaps the most commonly found members of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic cirrhosis. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

KRT18 links:

KRT8 (HGNC:6446): (keratin 8) This gene is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. The product of this gene typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. This protein plays a role in maintaining cellular structural integrity and also functions in signal transduction and cellular differentiation. Mutations in this gene cause cryptogenic cirrhosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

KRT8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

BP6

Variant 12-52949441-C-T is Benign according to our data. Variant chr12-52949441-C-T is described in ClinVar as [Benign]. Clinvar id is 1205845.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-52949441-C-T is described in Lovd as [Likely_benign]. Variant chr12-52949441-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT18	NM_000224.3 link	c.268C>T	p.Arg90Cys	missense_variant	Exon 1 of 7	ENST00000388835.4	NP_000215.1	P05783A0A024RAY2
KRT18	NM_199187.2 link	c.268C>T	p.Arg90Cys	missense_variant	Exon 2 of 8		NP_954657.1	P05783A0A024RAY2
KRT8	NM_001256293.2 link	c.-47+274G>A		intron_variant	Intron 1 of 8		NP_001243222.1	P05787-1
KRT8	NR_045962.2 link	n.405+15G>A		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT18	ENST00000388835.4 link	c.268C>T	p.Arg90Cys	missense_variant	Exon 1 of 7	1	NM_000224.3	ENSP00000373487.3		P05783

Frequencies

GnomAD3 genomes

AF:

0.467

AC:

41080

AN:

88004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.453

Gnomad AMI

AF:

0.486

Gnomad AMR

AF:

0.471

Gnomad ASJ

AF:

0.478

Gnomad EAS

AF:

0.452

Gnomad SAS

AF:

0.459

Gnomad FIN

AF:

0.474

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.474

Gnomad OTH

AF:

0.458

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000390

AC:

518

AN:

1328034

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

266

AN XY:

659270

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000264

AC:

AN:

30336

American (AMR)

AF:

0.000293

AC:

AN:

40924

Ashkenazi Jewish (ASJ)

AF:

0.000320

AC:

AN:

21858

East Asian (EAS)

AF:

0.000641

AC:

AN:

29642

South Asian (SAS)

AF:

0.000230

AC:

AN:

82528

European-Finnish (FIN)

AF:

0.00312

AC:

124

AN:

39748

Middle Eastern (MID)

AF:

0.0291

AC:

121

AN:

4162

European-Non Finnish (NFE)

AF:

0.000168

AC:

172

AN:

1026474

Other (OTH)

AF:

0.000688

AC:

AN:

52362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.251

Heterozygous variant carriers

162

243

324

405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff

AF:

0.467

AC:

41110

AN:

88086

Hom.:

Cov.:

AF XY:

0.466

AC XY:

20451

AN XY:

43920

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.453

AC:

10902

AN:

24064

American (AMR)

AF:

0.471

AC:

4144

AN:

8794

Ashkenazi Jewish (ASJ)

AF:

0.478

AC:

973

AN:

2036

East Asian (EAS)

AF:

0.452

AC:

1231

AN:

2724

South Asian (SAS)

AF:

0.459

AC:

1203

AN:

2622

European-Finnish (FIN)

AF:

0.474

AC:

3199

AN:

6748

Middle Eastern (MID)

AF:

0.467

AC:

AN:

122

European-Non Finnish (NFE)

AF:

0.474

AC:

18597

AN:

39254

Other (OTH)

AF:

0.458

AC:

536

AN:

1170

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.271

Heterozygous variant carriers

3931

7862

11792

15723

19654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.476

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.86

D;.;D

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.10

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

T;T;.

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.3

L;.;L

PhyloP100

7.9

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Pathogenic

0.70

Sift

Benign

0.058

T;D;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.0090

B;B;B

Vest4

0.98

MVP

0.99

MPC

0.72

ClinPred

0.97

GERP RS

2.9

PromoterAI

-0.037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.86

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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12-52949441-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over