rs200221269

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-52949307-G-A
• chr12-52949307-G-C
• chr12-52949307-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 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. Synonymous variant affecting the same amino acid position (i.e. R45R) has been classified as Likely benign.

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT18	NM_000224.3	c.134G>A	p.Arg45Gln	missense_variant	Exon 1 of 7	ENST00000388835.4	NP_000215.1
KRT18	NM_199187.2	c.134G>A	p.Arg45Gln	missense_variant	Exon 2 of 8		NP_954657.1
KRT8	NM_001256293.2	c.-47+408C>T		intron_variant	Intron 1 of 8		NP_001243222.1
KRT8	NR_045962.2	n.405+149C>T		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT18	ENST00000388835.4	c.134G>A	p.Arg45Gln	missense_variant	Exon 1 of 7	1	NM_000224.3	ENSP00000373487.3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 40

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-0.065
Eigen_PC	Benign	0.011
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.26	T;T;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.55	N;.;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.047	D;D;D
Sift4G	Benign	0.25	T;T;T
Polyphen		0.17	B;B;B
Vest4		0.50
MutPred		0.44		Gain of catalytic residue at G40 (P = 0);Gain of catalytic residue at G40 (P = 0);Gain of catalytic residue at G40 (P = 0);
MVP		0.79
MPC		0.62
ClinPred		0.50	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-53343091;