12-52949430-G-C

Variant names:

• chr12-52949430-G-C
• rs1188380011
• NM_000224.3:c.257G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000224.3(KRT18):​c.257G>C​(p.Ser86Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 40)
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33961576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT18	NM_000224.3	c.257G>C	p.Ser86Thr	missense_variant	Exon 1 of 7	ENST00000388835.4	NP_000215.1
KRT18	NM_199187.2	c.257G>C	p.Ser86Thr	missense_variant	Exon 2 of 8		NP_954657.1
KRT8	NM_001256293.2	c.-47+285C>G		intron_variant	Intron 1 of 8		NP_001243222.1
KRT8	NR_045962.2	n.405+26C>G		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT18	ENST00000388835.4	c.257G>C	p.Ser86Thr	missense_variant	Exon 1 of 7	1	NM_000224.3	ENSP00000373487.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152294 Hom.: 0 Cov.: 40

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152294 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 74414

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.257G>C (p.S86T) alteration is located in exon 1 (coding exon 1) of the KRT18 gene. This alteration results from a G to C substitution at nucleotide position 257, causing the serine (S) at amino acid position 86 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Uncertain	0.43	T;.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.91
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.27	T;T;.
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.78	N;.;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.25	B;B;B
Vest4		0.097
MutPred		0.47		Loss of MoRF binding (P = 0.1199);Loss of MoRF binding (P = 0.1199);Loss of MoRF binding (P = 0.1199);
MVP		0.59
MPC		0.59
ClinPred		0.20	T
GERP RS		-3.2
Varity_R		0.30
gMVP		0.54

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: rs1188380011; hg19: chr12-53343214;