12-52897442-C-T

Position:

chr12-52897442-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002273.4(KRT8):c.1438G>A(p.Val480Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,599,352 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0057 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 8 hom. )

Consequence

KRT8
NM_002273.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.851

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036435723).

BP6

Variant 12-52897442-C-T is Benign according to our data. Variant chr12-52897442-C-T is described in ClinVar as [Benign]. Clinvar id is 713128.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00569 (867/152254) while in subpopulation AFR AF= 0.0171 (709/41544). AF 95% confidence interval is 0.016. There are 7 homozygotes in gnomad4. There are 382 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT8	NM_002273.4 link	c.1438G>A	p.Val480Ile	missense_variant	8/8	ENST00000692008.1	NP_002264.1	P05787-1
KRT8	NM_001256282.2 link	c.1522G>A	p.Val508Ile	missense_variant	9/9		NP_001243211.1	Q7L4M3
KRT8	NM_001256293.2 link	c.1438G>A	p.Val480Ile	missense_variant	9/9		NP_001243222.1	P05787-1
KRT8	NR_045962.2 link	n.1889G>A		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT8	ENST00000692008.1 link	c.1438G>A	p.Val480Ile	missense_variant	8/8		NM_002273.4	ENSP00000509398.1		P05787-1

Frequencies

GnomAD3 genomes

AF:

0.00570

AC:

867

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00182

AC:

435

AN:

238674

Hom.:

AF XY:

0.00141

AC XY:

183

AN XY:

130050

show subpopulations

Gnomad AFR exome

AF:

0.0157

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000825

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00133

AC:

1921

AN:

1447098

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

886

AN XY:

720368

show subpopulations

Gnomad4 AFR exome

AF:

0.0175

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000126

Gnomad4 NFE exome

AF:

0.00105

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.00569

AC:

867

AN:

152254

Hom.:

Cov.:

AF XY:

0.00513

AC XY:

382

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0171

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000828

Hom.:

Bravo

AF:

0.00609

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0134

AC:

ESP6500EA

AF:

0.000754

AC:

ExAC

AF:

0.00222

AC:

268

EpiCase

AF:

0.00136

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

KRT8-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.66

DANN

Benign

0.90

DEOGEN2

Benign

0.20

T;T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.51

.;.;T;T

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.60

N;N;N;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.23

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.37

T;T;T;T

Sift4G

Benign

0.33

T;T;T;T

Polyphen

0.034

B;B;B;.

Vest4

0.11

MVP

0.64

MPC

0.43

ClinPred

0.0015

GERP RS

-0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.33

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