12-52949256-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000224.3(KRT18):c.83C>G(p.Pro28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000986 in 1,520,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P28L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 37)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

KRT18
NM_000224.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.23

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

cirrhosis, familial
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

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.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14230582).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000224.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT18	NM_000224.3	MANE Select	c.83C>G	p.Pro28Arg	missense	Exon 1 of 7	NP_000215.1	P05783
KRT18	NM_199187.2		c.83C>G	p.Pro28Arg	missense	Exon 2 of 8	NP_954657.1	P05783
KRT8	NM_001256293.2		c.-47+459G>C		intron	N/A	NP_001243222.1	P05787-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT18	ENST00000388835.4	TSL:1 MANE Select	c.83C>G	p.Pro28Arg	missense	Exon 1 of 7	ENSP00000373487.3	P05783
KRT18	ENST00000550600.5	TSL:1	c.83C>G	p.Pro28Arg	missense	Exon 2 of 7	ENSP00000447278.1	F8VZY9
KRT18	ENST00000872040.1		c.83C>G	p.Pro28Arg	missense	Exon 1 of 7	ENSP00000542099.1

Frequencies

GnomAD3 genomes

AF:

0.0000140

AC:

AN:

142832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000310

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

243652

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000943

AC:

AN:

1377880

Hom.:

Cov.:

AF XY:

0.0000102

AC XY:

AN XY:

685920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31474

American (AMR)

AF:

0.00

AC:

AN:

41572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24170

East Asian (EAS)

AF:

0.00

AC:

AN:

36424

South Asian (SAS)

AF:

0.000121

AC:

AN:

82778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3872

European-Non Finnish (NFE)

AF:

0.00000190

AC:

AN:

1055170

Other (OTH)

AF:

0.0000178

AC:

AN:

56246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000140

AC:

AN:

142832

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69632

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38558

American (AMR)

AF:

0.00

AC:

AN:

14318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3330

East Asian (EAS)

AF:

0.00

AC:

AN:

4778

South Asian (SAS)

AF:

0.00

AC:

AN:

4456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.0000310

AC:

AN:

64504

Other (OTH)

AF:

0.00

AC:

AN:

1934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000167

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.32

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.19

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.2

PhyloP100

1.2

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.1

REVEL

Benign

0.19

Sift

Benign

0.13

Sift4G

Benign

0.31

Polyphen

0.099

Vest4

0.23

MutPred

0.42

Gain of MoRF binding (P = 0.002)

MVP

0.53

MPC

0.60

ClinPred

0.051

GERP RS

2.8

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.076

gMVP

0.67

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over