12-52949441-C-T

Position:

• chr12-52949441-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PP3_Moderate BP6_Moderate

The NM_000224.3(KRT18):​c.268C>T​(p.Arg90Cys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.47 (0 hom., cov: 38)
  • Exomes 𝑓: 0.00039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 7.89

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 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• BP6: Variant 12-52949441-C-T is Benign according to our data. Variant chr12-52949441-C-T is described in ClinVar as [Benign]. Clinvar id is 1205845.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-52949441-C-T is described in Lovd as [Likely_benign]. Variant chr12-52949441-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT18	NM_000224.3	c.268C>T	p.Arg90Cys	missense_variant	1/7	ENST00000388835.4
KRT18	NM_199187.2	c.268C>T	p.Arg90Cys	missense_variant	2/8
KRT8	NM_001256293.2	c.-47+274G>A		intron_variant
KRT8	NR_045962.2	n.405+15G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT18	ENST00000388835.4	c.268C>T	p.Arg90Cys	missense_variant	1/7	1	NM_000224.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 41080 AN: 88004 Hom.: 0 Cov.: 38 FAILED QC

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.458

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000390 AC: 518 AN: 1328034 Hom.: 0 Cov.: 36 AF XY: 0.000403 AC XY: 266 AN XY: 659270

Gnomad4 AFR exome AF: 0.000264

Gnomad4 AMR exome AF: 0.000293

Gnomad4 ASJ exome AF: 0.000320

Gnomad4 EAS exome AF: 0.000641

Gnomad4 SAS exome AF: 0.000230

Gnomad4 FIN exome AF: 0.00312

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000688

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.467 AC: 41110 AN: 88086 Hom.: 0 Cov.: 38 AF XY: 0.466 AC XY: 20451 AN XY: 43920

Gnomad4 AFR AF: 0.453

Gnomad4 AMR AF: 0.471

Gnomad4 ASJ AF: 0.478

Gnomad4 EAS AF: 0.452

Gnomad4 SAS AF: 0.459

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.458

Alfa AF: 0.476 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D;.;D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;.
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.3	L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.058	T;D;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.0090	B;B;B
Vest4		0.98
MVP		0.99
MPC		0.72
ClinPred		0.97	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1397020078; hg19: chr12-53343225; COSMIC: COSV66315783; COSMIC: COSV66315783;