12-52950324-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000224.3(KRT18):c.418-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,608,378 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: KRT18 NM_000224.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001402
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.196

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS2: High AC in GnomAd at 124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT18	NM_000224.3	c.418-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000388835.4
KRT18	NM_199187.2	c.418-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT18	ENST00000388835.4	c.418-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000224.3	P1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00119 AC: 299 AN: 251408 Hom.: 0 AF XY: 0.00126 AC XY: 171 AN XY: 135884

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00114 AC: 1654 AN: 1456036 Hom.: 5 Cov.: 29 AF XY: 0.00119 AC XY: 859 AN XY: 724832

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00214

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74492

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.000914

EpiCase AF: 0.00185

EpiControl AF: 0.00237

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	2.9
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
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: rs267607652; hg19: chr12-53344108;