12-52949479-G-C

Position:

• chr12-52949479-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000224.3(KRT18):​c.306G>C​(p.Glu102Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 39)
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT18	NM_000224.3	c.306G>C	p.Glu102Asp	missense_variant	1/7	ENST00000388835.4	NP_000215.1
KRT18	NM_199187.2	c.306G>C	p.Glu102Asp	missense_variant	2/8		NP_954657.1
KRT8	NM_001256293.2	c.-47+236C>G		intron_variant			NP_001243222.1
KRT8	NR_045962.2	n.382C>G		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT18	ENST00000388835.4	c.306G>C	p.Glu102Asp	missense_variant	1/7	1	NM_000224.3	ENSP00000373487.3

Frequencies

GnomAD3 genomes Cov.: 39

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 39

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.306G>C (p.E102D) 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 306, causing the glutamic acid (E) at amino acid position 102 to be replaced by an aspartic acid (D). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;D
Eigen	Benign	0.17
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.70	T;T;.
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.8	H;.;H
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Pathogenic	0.82
Sift	Benign	0.031	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.93	P;P;P
Vest4		0.56
MutPred		0.70		Gain of MoRF binding (P = 0.127);Gain of MoRF binding (P = 0.127);Gain of MoRF binding (P = 0.127);
MVP		1.0
MPC		0.92
ClinPred		0.98	D
GERP RS		0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-53343263;