rs57749775

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_002273.4(KRT8):c.160T>C(p.Tyr54His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,612,398 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y54C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0066 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 9 hom. )

Consequence

KRT8
NM_002273.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:2O:2

Conservation

PhyloP100: 0.392

Variant links:

Genes affected

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 Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.06538835).

BP6

Variant 12-52904822-A-G is Benign according to our data. Variant chr12-52904822-A-G is described in ClinVar as [Benign]. Clinvar id is 14631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00658 (1001/152232) while in subpopulation AFR AF= 0.023 (954/41550). AF 95% confidence interval is 0.0218. There are 10 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KRT8	NM_002273.4 linkuse as main transcript	c.160T>C	p.Tyr54His	missense_variant	1/8	ENST00000692008.1
KRT8	NM_001256282.2 linkuse as main transcript	c.244T>C	p.Tyr82His	missense_variant	2/9
KRT8	NM_001256293.2 linkuse as main transcript	c.160T>C	p.Tyr54His	missense_variant	2/9
KRT8	NR_045962.2 linkuse as main transcript	n.611T>C		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT8	ENST00000692008.1 linkuse as main transcript	c.160T>C	p.Tyr54His	missense_variant	1/8		NM_002273.4	P2	P05787-1

Frequencies

GnomAD3 genomes

AF:

0.00658

AC:

1001

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00170

AC:

421

AN:

248332

Hom.:

AF XY:

0.00136

AC XY:

184

AN XY:

134908

show subpopulations

Gnomad AFR exome

AF:

0.0229

Gnomad AMR exome

AF:

0.00156

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:

0.0000805

Gnomad OTH exome

AF:

0.000985

GnomAD4 exome

AF:

0.000655

AC:

956

AN:

1460166

Hom.:

Cov.:

AF XY:

0.000613

AC XY:

445

AN XY:

726402

show subpopulations

Gnomad4 AFR exome

AF:

0.0219

Gnomad4 AMR exome

AF:

0.00190

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.00149

GnomAD4 genome

AF:

0.00658

AC:

1001

AN:

152232

Hom.:

Cov.:

AF XY:

0.00633

AC XY:

471

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0230

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00262

Hom.:

Bravo

AF:

0.00717

ESP6500AA

AF:

0.0147

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.00199

AC:

241

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:2Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cirrhosis, cryptogenic

Uncertain:1Other:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	May 24, 2001	- -
risk factor, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_002273.3:c.160T>C in the KRT8 gene has an allele frequency of 0.022 in African subpopulation in the gnomAD database. Two patients with liver disease or noncryptogenic chronic or acute liver disease were found to have this variant (PMID: 11372009). The author proposed that mutations in the keratin 8 gene may predispose people to liver disease (PMID: 11372009; PMID: 12724528). Taken together, we interprete this variant as risk factor variant. -

not specified

Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.051, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Hepatitis C virus, susceptibility to

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

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

0.26

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.17

Cadd

Benign

Dann

Benign

0.80

DEOGEN2

Uncertain

0.66

D;D;D;.;.;T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.29

MetaRNN

Benign

0.065

T;T;T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.9

M;M;M;.;.;.;.

MutationTaster

Benign

0.0042

A;A;A;A;A

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.2

D;D;D;D;D;D;D

REVEL

Uncertain

0.34

Sift

Benign

0.045

D;D;D;D;D;D;D

Sift4G

Benign

0.063

T;T;T;T;.;.;D

Polyphen

0.0070

B;B;B;.;.;.;.

Vest4

0.74

MVP

0.87

MPC

0.73

ClinPred

0.043

GERP RS

2.1

Varity_R

0.17

gMVP

0.56

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.

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