12-52904798-C-G

Variant names:

• chr12-52904798-C-G
• rs11554495
• NM_002273.4:c.184G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002273.4(KRT8):​c.184G>C​(p.Gly62Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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)
• Consequence: KRT8 NM_002273.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.761
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT8	NM_002273.4	c.184G>C	p.Gly62Arg	missense_variant	Exon 1 of 8	ENST00000692008.1	NP_002264.1
KRT8	NM_001256282.2	c.268G>C	p.Gly90Arg	missense_variant	Exon 2 of 9		NP_001243211.1
KRT8	NM_001256293.2	c.184G>C	p.Gly62Arg	missense_variant	Exon 2 of 9		NP_001243222.1
KRT8	NR_045962.2	n.635G>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	c.184G>C	p.Gly62Arg	missense_variant	Exon 1 of 8		NM_002273.4	ENSP00000509398.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D;D;.;.;T;T
Eigen	Benign	0.14
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.72	.;.;T;T;T;T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.9	H;H;H;.;.;.;.
PhyloP100		0.76
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;.;.;D
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.42
MutPred		0.73		Gain of methylation at G62 (P = 0.0218);Gain of methylation at G62 (P = 0.0218);Gain of methylation at G62 (P = 0.0218);.;Gain of methylation at G62 (P = 0.0218);.;.;
MVP		0.95
MPC		1.5
ClinPred		0.95	D
GERP RS		1.7
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.44
gMVP		0.86
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs11554495; hg19: chr12-53298582;