12-52949307-G-T

Variant names:

• chr12-52949307-G-T
• rs200221269
• NM_000224.3:c.134G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_000224.3(KRT18):​c.134G>T​(p.Arg45Leu) variant causes a missense change. 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. R45P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 40)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.05
• 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.

• PM1: In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity K1C18_HUMAN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

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.134G>T	p.Arg45Leu	missense	Exon 1 of 7	NP_000215.1	P05783
	KRT18	NM_199187.2		c.134G>T	p.Arg45Leu	missense	Exon 2 of 8	NP_954657.1	P05783
	KRT8	NM_001256293.2		c.-47+408C>A		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.134G>T	p.Arg45Leu	missense	Exon 1 of 7	ENSP00000373487.3	P05783
	KRT18	ENST00000550600.5	TSL:1	c.134G>T	p.Arg45Leu	missense	Exon 2 of 7	ENSP00000447278.1	F8VZY9
	KRT18	ENST00000872040.1		c.134G>T	p.Arg45Leu	missense	Exon 1 of 7	ENSP00000542099.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152270 Hom.: 0 Cov.: 40

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458086 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 725338

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4204

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111724

Other (OTH) AF: 0.00 AC: 0 AN: 60178

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000656 AC: 1 AN: 152388 Hom.: 0 Cov.: 40 AF XY: 0.0000134 AC XY: 1 AN XY: 74516

African (AFR) AF: 0.00 AC: 0 AN: 41602

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2116

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	0.067
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.26	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.22	T
Polyphen		0.049	B
Vest4		0.70
MutPred		0.55		Gain of catalytic residue at G40 (P = 0)
MVP		0.79
MPC		0.68
ClinPred		0.97	D
GERP RS		3.7
PromoterAI		-0.086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.85
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200221269; hg19: chr12-53343091;