12-52949307-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_000224.3(KRT18):c.134G>C(p.Arg45Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,610,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. R45R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 40)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: not provided no classification provided O:1
• 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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity K1C18_HUMAN
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT18	NM_000224.3	c.134G>C	p.Arg45Pro	missense_variant	1/7	ENST00000388835.4
KRT18	NM_199187.2	c.134G>C	p.Arg45Pro	missense_variant	2/8
KRT8	NM_001256293.2	c.-47+408C>G		intron_variant
KRT8	NR_045962.2	n.405+149C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT18	ENST00000388835.4	c.134G>C	p.Arg45Pro	missense_variant	1/7	1	NM_000224.3	P1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152274 Hom.: 0 Cov.: 40

Gnomad AFR AF: 0.0000964

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: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 26 AN: 243312 Hom.: 0 AF XY: 0.000113 AC XY: 15 AN XY: 133138

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000177 AC: 258 AN: 1458088 Hom.: 0 Cov.: 36 AF XY: 0.000174 AC XY: 126 AN XY: 725338

Gnomad4 AFR exome AF: 0.0000299

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: 0.000228

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152274 Hom.: 0 Cov.: 40 AF XY: 0.000148 AC XY: 11 AN XY: 74392

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000151 Hom.: 0

ExAC AF: 0.0000834 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Hepatitis C virus, susceptibility to Other:1

not provided, no classification provided

literature only

STRNAD Lab, University Hospital of Ulm

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D;.;D
Eigen	Benign	0.033
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.23	T;T;.
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.049	B;B;B
Vest4		0.67
MVP		0.81
MPC		0.78
ClinPred		0.095	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs200221269; hg19: chr12-53343091; COSMIC: COSV66315965; COSMIC: COSV66315965;