Genetic Variant KRT8:p.Gly62Ser (chr12-52904798-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002273.4(KRT8):c.184G>A(p.Gly62Ser) 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 1,460,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. G62C) has been classified as Likely 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: 0.761

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41418207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KRT8	NM_002273.4 link	c.184G>A	p.Gly62Ser	missense_variant	Exon 1 of 8	ENST00000692008.1	NP_002264.1
KRT8	NM_001256282.2 link	c.268G>A	p.Gly90Ser	missense_variant	Exon 2 of 9		NP_001243211.1
KRT8	NM_001256293.2 link	c.184G>A	p.Gly62Ser	missense_variant	Exon 2 of 9		NP_001243222.1
KRT8	NR_045962.2 link	n.635G>A		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.184G>A	p.Gly62Ser	missense_variant	Exon 1 of 8		NM_002273.4	ENSP00000509398.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460028

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52782

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4870

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111930

Other (OTH)

AF:

0.00

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Benign

0.12

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

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

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.70

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

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.41

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

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.3

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

PhyloP100

0.76

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-4.2

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

REVEL

Uncertain

0.39

Sift

Benign

0.097

T;T;T;T;D;D;T

Sift4G

Benign

0.074

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

Polyphen

0.29

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

Vest4

0.082

MutPred

0.44

Gain of glycosylation at G62 (P = 0.0311);Gain of glycosylation at G62 (P = 0.0311);Gain of glycosylation at G62 (P = 0.0311);.;Gain of glycosylation at G62 (P = 0.0311);.;.;

MVP

0.91

MPC

0.73

ClinPred

0.60

GERP RS

1.7

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.19

gMVP

0.84

Mutation Taster

=86/14

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over