rs76301931

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000224.3(KRT18):ā€‹c.11C>Gā€‹(p.Thr4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000837 in 1,194,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 25)
Exomes š‘“: 8.4e-7 ( 0 hom. )

Consequence

KRT18
NM_000224.3 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0630
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.067687005).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRT18NM_000224.3 linkc.11C>G p.Thr4Ser missense_variant Exon 1 of 7 ENST00000388835.4 NP_000215.1 P05783A0A024RAY2
KRT18NM_199187.2 linkc.11C>G p.Thr4Ser missense_variant Exon 2 of 8 NP_954657.1 P05783A0A024RAY2
KRT8NM_001256293.2 linkc.-47+531G>C intron_variant Intron 1 of 8 NP_001243222.1 P05787-1
KRT8NR_045962.2 linkn.405+272G>C intron_variant Intron 1 of 8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRT18ENST00000388835.4 linkc.11C>G p.Thr4Ser missense_variant Exon 1 of 7 1 NM_000224.3 ENSP00000373487.3 P05783

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD3 exomes
AF:
0.00000405
AC:
1
AN:
246676
Hom.:
0
AF XY:
0.00000745
AC XY:
1
AN XY:
134238
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 SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
8.37e-7
AC:
1
AN:
1194910
Hom.:
0
Cov.:
35
AF XY:
0.00000168
AC XY:
1
AN XY:
595514
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
25
ExAC
AF:
0.00000826
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
14
DANN
Benign
0.80
DEOGEN2
Benign
0.092
T;.;T
Eigen
Benign
-0.87
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.59
D
LIST_S2
Benign
0.53
T;T;.
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.068
T;T;T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
1.2
L;.;L
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.32
N;N;N
REVEL
Benign
0.11
Sift
Benign
0.44
T;T;T
Sift4G
Benign
0.51
T;T;T
Polyphen
0.047
B;B;B
Vest4
0.12
MutPred
0.27
Gain of catalytic residue at S7 (P = 0.0267);Gain of catalytic residue at S7 (P = 0.0267);Gain of catalytic residue at S7 (P = 0.0267);
MVP
0.62
MPC
0.53
ClinPred
0.073
T
GERP RS
0.94
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.044
gMVP
0.37

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

LitVar

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

Other links and lift over

dbSNP: rs76301931; hg19: chr12-53342968; API