Genetic Variant KRT18:p.Ala92Ser (chr12-52949447-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000224.3(KRT18):c.274G>T(p.Ala92Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,432,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A92P) has been classified as Benign.

Frequency

Genomes: not found (cov: 38)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KRT18
NM_000224.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.62

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT18	NM_000224.3 link	c.274G>T	p.Ala92Ser	missense_variant	Exon 1 of 7	ENST00000388835.4	NP_000215.1	P05783A0A024RAY2
KRT18	NM_199187.2 link	c.274G>T	p.Ala92Ser	missense_variant	Exon 2 of 8		NP_954657.1	P05783A0A024RAY2
KRT8	NM_001256293.2 link	c.-47+268C>A		intron_variant	Intron 1 of 8		NP_001243222.1	P05787-1
KRT8	NR_045962.2 link	n.405+9C>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.274G>T	p.Ala92Ser	missense_variant	Exon 1 of 7	1	NM_000224.3	ENSP00000373487.3		P05783

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1432758

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32776

American (AMR)

AF:

0.00

AC:

AN:

44022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25360

East Asian (EAS)

AF:

0.00

AC:

AN:

38056

South Asian (SAS)

AF:

0.00

AC:

AN:

85552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5090

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1093618

Other (OTH)

AF:

0.00

AC:

AN:

58658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D;.

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;.;M

PhyloP100

5.6

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Pathogenic

0.90

Sift

Uncertain

0.024

D;D;D

Sift4G

Uncertain

0.026

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.32

MutPred

0.68

Gain of phosphorylation at A92 (P = 0.0152);Gain of phosphorylation at A92 (P = 0.0152);Gain of phosphorylation at A92 (P = 0.0152);

MVP

0.88

MPC

1.2

ClinPred

0.99

GERP RS

3.8

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.82

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over