12-52949455-C-G

Variant names:

• chr12-52949455-C-G
• rs386834224
• NM_000224.3:c.282C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000224.3(KRT18):​c.282C>G​(p.Tyr94*) variant causes a stop gained 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. Synonymous variant affecting the same amino acid position (i.e. Y94Y) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 40)
  • Failed GnomAD Quality Control
• Consequence: KRT18 NM_000224.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27
• Publications: 0 publications found

Genes affected

KRT18 (HGNC:6430): (keratin 18) KRT18 encodes the type I intermediate filament chain keratin 18. Keratin 18, together with its filament partner keratin 8, are perhaps the most commonly found members of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic cirrhosis. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000224.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT18	NM_000224.3	MANE Select	c.282C>G	p.Tyr94*	stop_gained	Exon 1 of 7	NP_000215.1	P05783
	KRT18	NM_199187.2		c.282C>G	p.Tyr94*	stop_gained	Exon 2 of 8	NP_954657.1	P05783
	KRT8	NM_001256293.2		c.-47+260G>C		intron	N/A	NP_001243222.1	P05787-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT18	ENST00000388835.4	TSL:1 MANE Select	c.282C>G	p.Tyr94*	stop_gained	Exon 1 of 7	ENSP00000373487.3	P05783
	KRT18	ENST00000550600.5	TSL:1	c.282C>G	p.Tyr94*	stop_gained	Exon 2 of 7	ENSP00000447278.1	F8VZY9
	KRT18	ENST00000872040.1		c.282C>G	p.Tyr94*	stop_gained	Exon 1 of 7	ENSP00000542099.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152272 Hom.: 0 Cov.: 40

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152272 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 74394

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68052

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		2.3
GERP RS		0.97
PromoterAI		-0.18	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=18/182	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386834224; hg19: chr12-53343239;