12-52949307-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000224.3(KRT18):​c.134G>A​(p.Arg45Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,088 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. R45P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 40)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33052278).

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>A	p.Arg45Gln	missense	Exon 1 of 7	NP_000215.1	P05783
	KRT18	NM_199187.2		c.134G>A	p.Arg45Gln	missense	Exon 2 of 8	NP_954657.1	P05783
	KRT8	NM_001256293.2		c.-47+408C>T		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>A	p.Arg45Gln	missense	Exon 1 of 7	ENSP00000373487.3	P05783
	KRT18	ENST00000550600.5	TSL:1	c.134G>A	p.Arg45Gln	missense	Exon 2 of 7	ENSP00000447278.1	F8VZY9
	KRT18	ENST00000872040.1		c.134G>A	p.Arg45Gln	missense	Exon 1 of 7	ENSP00000542099.1

Frequencies

GnomAD3 genomes Cov.: 40

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458088 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: 51952

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111724

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

GnomAD4 genome Cov.: 40

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.065
Eigen_PC	Benign	0.011
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.26	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.55	N
PhyloP100		5.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.047	D
Sift4G	Benign	0.25	T
Polyphen		0.17	B
Vest4		0.50
MutPred		0.44		Gain of catalytic residue at G40 (P = 0)
MVP		0.79
MPC		0.62
ClinPred		0.50	D
GERP RS		3.7
PromoterAI		-0.082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.77
Mutation Taster		=85/15	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: rs200221269; hg19: chr12-53343091;