12-52904822-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 12/21 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

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

cirrhosis, familial
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

KRT8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KRT8	NM_002273.4 link	c.160T>C	p.Tyr54His	missense_variant	Exon 1 of 8	ENST00000692008.1	NP_002264.1
KRT8	NM_001256282.2 link	c.244T>C	p.Tyr82His	missense_variant	Exon 2 of 9		NP_001243211.1
KRT8	NM_001256293.2 link	c.160T>C	p.Tyr54His	missense_variant	Exon 2 of 9		NP_001243222.1
KRT8	NR_045962.2 link	n.611T>C		non_coding_transcript_exon_variant	Exon 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT8	ENST00000692008.1 link	c.160T>C	p.Tyr54His	missense_variant	Exon 1 of 8		NM_002273.4	ENSP00000509398.1

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

GnomAD2 exomes

AF:

0.00170

AC:

421

AN:

248332

AF XY:

0.00136

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 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

African (AFR)

AF:

0.0219

AC:

732

AN:

33438

American (AMR)

AF:

0.00190

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52730

Middle Eastern (MID)

AF:

0.00119

AC:

AN:

5030

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1111942

Other (OTH)

AF:

0.00149

AC:

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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

AF:

0.00658

AC:

1001

AN:

152232

Hom.:

Cov.:

AF XY:

0.00633

AC XY:

471

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0230

AC:

954

AN:

41550

American (AMR)

AF:

0.00222

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68012

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

133

177

221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00219

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

May 24, 2001

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:curation

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

Oct 28, 2020

H3Africa Consortium

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

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

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

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

(source)

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

LIST_S2

Benign

0.0

.;.;T;T;T;T;T

MetaRNN

Benign

0.065

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

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.9

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

PhyloP100

0.39

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

Vest4

0.74

ClinPred

0.043

GERP RS

2.1

PromoterAI

0.22

Neutral

(source)

Varity_R

0.17

gMVP

0.56

Mutation Taster

=94/6

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over