chr12-52949556-A-T

Position:

chr12-52949556-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_000224.3(KRT18):c.383A>T(p.His128Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,856 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic,risk factor (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 3 hom. )

Consequence

KRT18
NM_000224.3 missense

Scores

Clinical Significance

Pathogenic; risk factor no assertion criteria provided P:1O:2

Conservation

PhyloP100: 1.69

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 12-52949556-A-T is Pathogenic according to our data. Variant chr12-52949556-A-T is described in ClinVar as [Pathogenic, risk_factor]. Clinvar id is 14585.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0725455). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KRT18	NM_000224.3 linkuse as main transcript	c.383A>T	p.His128Leu	missense_variant	1/7	ENST00000388835.4
KRT18	NM_199187.2 linkuse as main transcript	c.383A>T	p.His128Leu	missense_variant	2/8
KRT8	NM_001256293.2 linkuse as main transcript	c.-47+159T>A		intron_variant
KRT8	NR_045962.2 linkuse as main transcript	n.305T>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT18	ENST00000388835.4 linkuse as main transcript	c.383A>T	p.His128Leu	missense_variant	1/7	1	NM_000224.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000633

AC:

158

AN:

249414

Hom.:

AF XY:

0.000672

AC XY:

AN XY:

135476

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0125

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000231

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.000323

AC:

472

AN:

1461646

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

251

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0124

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000620

Gnomad4 OTH exome

AF:

0.00127

GnomAD4 genome

AF:

0.000309

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00216

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.000429

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic; risk factor

Submissions summary: Pathogenic:1Other:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Cirrhosis, cryptogenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 13, 2003

- -

Cirrhosis, noncryptogenic, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 13, 2003

- -

not provided

Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.72

D;.;D

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.66

T;T;.

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.073

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.86

L;.;L

MutationTaster

Benign

0.0095

A;A;A;A;A

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-4.6

D;D;D

REVEL

Uncertain

0.53

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.33

T;T;T

Polyphen

0.014

B;B;B

Vest4

0.50

MVP

1.0

MPC

0.79

ClinPred

0.047

GERP RS

1.2

Varity_R

0.29

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over