12-52949307-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The NM_000224.3(KRT18):ā€‹c.134G>Cā€‹(p.Arg45Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,610,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. R45R) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.00018 ( 0 hom., cov: 40)
Exomes š‘“: 0.00018 ( 0 hom. )

Consequence

KRT18
NM_000224.3 missense

Scores

2
11
6

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 5.05
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1
In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity K1C18_HUMAN
BS2
High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KRT18NM_000224.3 linkuse as main transcriptc.134G>C p.Arg45Pro missense_variant 1/7 ENST00000388835.4
KRT18NM_199187.2 linkuse as main transcriptc.134G>C p.Arg45Pro missense_variant 2/8
KRT8NM_001256293.2 linkuse as main transcriptc.-47+408C>G intron_variant
KRT8NR_045962.2 linkuse as main transcriptn.405+149C>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KRT18ENST00000388835.4 linkuse as main transcriptc.134G>C p.Arg45Pro missense_variant 1/71 NM_000224.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152274
Hom.:
0
Cov.:
40
show subpopulations
Gnomad AFR
AF:
0.0000964
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:
0.000338
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000107
AC:
26
AN:
243312
Hom.:
0
AF XY:
0.000113
AC XY:
15
AN XY:
133138
show subpopulations
Gnomad AFR exome
AF:
0.000139
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000211
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.000177
AC:
258
AN:
1458088
Hom.:
0
Cov.:
36
AF XY:
0.000174
AC XY:
126
AN XY:
725338
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000228
Gnomad4 OTH exome
AF:
0.0000499
GnomAD4 genome
AF:
0.000177
AC:
27
AN:
152274
Hom.:
0
Cov.:
40
AF XY:
0.000148
AC XY:
11
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.0000964
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000338
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000151
Hom.:
0
ExAC
AF:
0.0000834
AC:
10
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

Hepatitis C virus, susceptibility to Other:1
not provided, no classification providedliterature onlySTRNAD Lab, University Hospital of Ulm-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Benign
-0.046
T
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.53
D;.;D
Eigen
Benign
0.033
Eigen_PC
Benign
0.072
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.23
T;T;.
M_CAP
Pathogenic
0.30
D
MetaRNN
Uncertain
0.70
D;D;D
MetaSVM
Uncertain
0.073
D
MutationAssessor
Uncertain
2.1
M;.;M
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.8
D;D;D
REVEL
Uncertain
0.52
Sift
Uncertain
0.0050
D;D;D
Sift4G
Benign
0.11
T;T;T
Polyphen
0.049
B;B;B
Vest4
0.67
MVP
0.81
MPC
0.78
ClinPred
0.095
T
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.59
gMVP
0.86

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200221269; hg19: chr12-53343091; COSMIC: COSV66315965; COSMIC: COSV66315965; API