12-52949447-G-C

Position:

• chr12-52949447-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PP3_Strong BP6_Moderate

The NM_000224.3(KRT18):​c.274G>C​(p.Ala92Pro) variant causes a missense change. 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: 0.00038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 5.62

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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• BP6: Variant 12-52949447-G-C is Benign according to our data. Variant chr12-52949447-G-C is described in ClinVar as [Benign]. Clinvar id is 1205843.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-52949447-G-C is described in Lovd as [Likely_benign]. Variant chr12-52949447-G-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT18	NM_000224.3	c.274G>C	p.Ala92Pro	missense_variant	1/7	ENST00000388835.4
KRT18	NM_199187.2	c.274G>C	p.Ala92Pro	missense_variant	2/8
KRT8	NM_001256293.2	c.-47+268C>G		intron_variant
KRT8	NR_045962.2	n.405+9C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT18	ENST00000388835.4	c.274G>C	p.Ala92Pro	missense_variant	1/7	1	NM_000224.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 40011 AN: 85882 Hom.: 0 Cov.: 38 FAILED QC

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.456

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000383 AC: 508 AN: 1328096 Hom.: 0 Cov.: 36 AF XY: 0.000410 AC XY: 270 AN XY: 659320

Gnomad4 AFR exome AF: 0.000231

Gnomad4 AMR exome AF: 0.000195

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.000848

Gnomad4 SAS exome AF: 0.000230

Gnomad4 FIN exome AF: 0.00278

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.000689

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.466 AC: 40039 AN: 85958 Hom.: 0 Cov.: 38 AF XY: 0.465 AC XY: 19905 AN XY: 42852

Gnomad4 AFR AF: 0.451

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.479

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.459

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.456

Alfa AF: 0.438 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

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

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	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;.
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.87
MVP		0.96
MPC		1.7
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1434610693; hg19: chr12-53343231; COSMIC: COSV66315787; COSMIC: COSV66315787;