12-52951512-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000224.3(KRT18):c.689G>C(p.Ser230Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00569 in 1,614,086 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (41 hom.)
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2 O:1
• Conservation: PhyloP100: 0.910

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00872156).
• BP6: Variant 12-52951512-G-C is Benign according to our data. Variant chr12-52951512-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 66138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-52951512-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 607 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT18	NM_000224.3	c.689G>C	p.Ser230Thr	missense_variant	4/7	ENST00000388835.4
KRT18	NM_199187.2	c.689G>C	p.Ser230Thr	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT18	ENST00000388835.4	c.689G>C	p.Ser230Thr	missense_variant	4/7	1	NM_000224.3	P1

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 607 AN: 152222 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00636

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00360 AC: 904 AN: 251354 Hom.: 5 AF XY: 0.00381 AC XY: 518 AN XY: 135892

Gnomad AFR exome AF: 0.000925

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00605

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00587 AC: 8575 AN: 1461746 Hom.: 41 Cov.: 33 AF XY: 0.00573 AC XY: 4169 AN XY: 727184

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.000992

Gnomad4 NFE exome AF: 0.00701

Gnomad4 OTH exome AF: 0.00598

GnomAD4 genome AF: 0.00398 AC: 606 AN: 152340 Hom.: 3 Cov.: 32 AF XY: 0.00369 AC XY: 275 AN XY: 74502

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00555

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00635

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00487 Hom.: 2

Bravo AF: 0.00362

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00359 AC: 436

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00522

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KRT18 p.Ser230Thr variant was not identified in the literature nor was it identified in Cosmic, however it was identified in dbSNP (ID: rs58472472), ClinVar (clinical significance not provided) and LOVD 3.0. The variant was identified in control databases in 1028 of 282750 chromosomes (6 homozygous) at a frequency of 0.003636 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 785 of 129112 chromosomes (freq: 0.00608), Other in 25 of 7214 chromosomes (freq: 0.003465), Latino in 91 of 35440 chromosomes (freq: 0.002568), South Asian in 58 of 30616 chromosomes (freq: 0.001894), African in 33 of 24930 chromosomes (freq: 0.001324), European (Finnish) in 26 of 25120 chromosomes (freq: 0.001035) and Ashkenazi Jewish in 10 of 10370 chromosomes (freq: 0.000964); it was not observed in the East Asian population. This variant was identified in 2/329 German patients with chronic hepatitis C, 2/344 patients with acute liver failure and 4/97 patients with IBD (Strnad_2006_PMID: 16729313; Strnad_2010_PMID: 20538000; Owens_2004_PMID: 15090596). However it should be noted that the authors from these studies referred to this variant as a polymorphism rather than a mutation and did not suspect significant biological relevance. Further, functional in vitro studies of this variant in cell models suggested conflicting results regarding the potential pathogenicity of this variant (Owens_2004_PMID: 15090596; Zupancic_2014_PMID: 24915158). The p.Ser230 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	KRT18: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.;T
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.70	T;T;.
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.43	B;P;B
Vest4		0.20
MVP		0.70
MPC		0.60
ClinPred		0.019	T
GERP RS		0.26
Varity_R		0.37
gMVP		0.39

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: rs58472472; hg19: chr12-53345296; COSMIC: COSV101184200; COSMIC: COSV101184200;