Genetic Variant NM_000224.3:c.83C>T (chr12-52949256-C-T) – ACMG Classification: Uncertain_significance (0 pts)

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>T(p.Pro28Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 37)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRT18
NM_000224.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23

Publications

0 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:

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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=0.17784524).

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>T	p.Pro28Leu	missense	Exon 1 of 7	NP_000215.1	P05783
KRT18	NM_199187.2		c.83C>T	p.Pro28Leu	missense	Exon 2 of 8	NP_954657.1	P05783
KRT8	NM_001256293.2		c.-47+459G>A		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>T	p.Pro28Leu	missense	Exon 1 of 7	ENSP00000373487.3	P05783
KRT18	ENST00000550600.5	TSL:1	c.83C>T	p.Pro28Leu	missense	Exon 2 of 7	ENSP00000447278.1	F8VZY9
KRT18	ENST00000872040.1		c.83C>T	p.Pro28Leu	missense	Exon 1 of 7	ENSP00000542099.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1377878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

685920

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:

0.00

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:

0.00

AC:

AN:

1055168

Other (OTH)

AF:

0.00

AC:

AN:

56246

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.18

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.98

PhyloP100

1.2

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.21

Sift

Uncertain

0.028

Sift4G

Benign

0.58

Polyphen

0.095

Vest4

0.25

MutPred

0.42

Loss of loop (P = 0.0112)

MVP

0.62

MPC

0.54

ClinPred

0.14

GERP RS

2.8

PromoterAI

-0.055

Neutral

(source)

Varity_R

0.10

gMVP

0.61

Mutation Taster

=93/7

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over