12-52949473-C-G

Position:

• chr12-52949473-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4 BP6_Moderate

The NM_000224.3(KRT18):​c.300C>G​(p.Ser100Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.44 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.827

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36624002).
• BP6: Variant 12-52949473-C-G is Benign according to our data. Variant chr12-52949473-C-G is described in ClinVar as [Benign]. Clinvar id is 1205851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-52949473-C-G is described in Lovd as [Likely_benign]. Variant chr12-52949473-C-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT18	NM_000224.3	c.300C>G	p.Ser100Arg	missense_variant	1/7	ENST00000388835.4
KRT18	NM_199187.2	c.300C>G	p.Ser100Arg	missense_variant	2/8
KRT8	NM_001256293.2	c.-47+242G>C		intron_variant
KRT8	NR_045962.2	n.388G>C		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT18	ENST00000388835.4	c.300C>G	p.Ser100Arg	missense_variant	1/7	1	NM_000224.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 30737 AN: 69580 Hom.: 0 Cov.: 36 FAILED QC

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.435

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.420

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000207 AC: 279 AN: 1350270 Hom.: 0 Cov.: 36 AF XY: 0.000239 AC XY: 160 AN XY: 670688

Gnomad4 AFR exome AF: 0.0000974

Gnomad4 AMR exome AF: 0.0000720

Gnomad4 ASJ exome AF: 0.0000446

Gnomad4 EAS exome AF: 0.000388

Gnomad4 SAS exome AF: 0.000250

Gnomad4 FIN exome AF: 0.00203

Gnomad4 NFE exome AF: 0.0000529

Gnomad4 OTH exome AF: 0.000373

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.442 AC: 30761 AN: 69652 Hom.: 0 Cov.: 36 AF XY: 0.441 AC XY: 15376 AN XY: 34904

Gnomad4 AFR AF: 0.420

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.458

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.429

Gnomad4 FIN AF: 0.456

Gnomad4 NFE AF: 0.452

Gnomad4 OTH AF: 0.420

Alfa AF: 0.475 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0067	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.46	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	-0.038	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	0.21	N;.
REVEL	Benign	0.19
Sift	Uncertain	0.024	D;.
Vest4		0.47
MutPred		0.63		Loss of MoRF binding (P = 0.0303);Loss of MoRF binding (P = 0.0303);
MVP		0.75
ClinPred		0.89	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs796361379; hg19: chr12-53343257; COSMIC: COSV66315790; COSMIC: COSV66315790;