Genetic Variant NM_002273.4:c.160T>G (chr12-52904822-A-C) – 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_002273.4(KRT8):c.160T>G(p.Tyr54Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,166 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. Y54H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KRT8
NM_002273.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.392

Publications

0 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: 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
KRT8	NM_002273.4 link	c.160T>G	p.Tyr54Asp	missense_variant	Exon 1 of 8	ENST00000692008.1	NP_002264.1	P05787-1
KRT8	NM_001256282.2 link	c.244T>G	p.Tyr82Asp	missense_variant	Exon 2 of 9		NP_001243211.1	Q7L4M3
KRT8	NM_001256293.2 link	c.160T>G	p.Tyr54Asp	missense_variant	Exon 2 of 9		NP_001243222.1	P05787-1
KRT8	NR_045962.2 link	n.611T>G		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>G	p.Tyr54Asp	missense_variant	Exon 1 of 8		NM_002273.4	ENSP00000509398.1		P05787-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726402

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

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:

0.0000116

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5030

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111942

Other (OTH)

AF:

0.00

AC:

AN:

60298

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.71

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

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.074

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

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.51

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

MetaSVM

Uncertain

-0.068

MutationAssessor

Pathogenic

3.6

H;H;H;.;.;.;.

PhyloP100

0.39

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.2

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

REVEL

Uncertain

0.39

Sift

Uncertain

0.017

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

Sift4G

Uncertain

0.024

D;D;D;D;.;.;D

Polyphen

0.59

P;P;P;.;.;.;.

Vest4

0.46

MutPred

0.54

Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);.;Gain of disorder (P = 0.0544);.;.;

MVP

0.91

MPC

1.7

ClinPred

0.50

GERP RS

2.1

PromoterAI

0.00080

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.65

gMVP

0.71

Mutation Taster

=88/12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over