12-52949473-C-A

Variant names:

• chr12-52949473-C-A
• rs796361379
• NM_000224.3:c.300C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000224.3(KRT18):​c.300C>A​(p.Ser100Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 10/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT18	NM_000224.3	c.300C>A	p.Ser100Arg	missense_variant	Exon 1 of 7	ENST00000388835.4	NP_000215.1
KRT18	NM_199187.2	c.300C>A	p.Ser100Arg	missense_variant	Exon 2 of 8		NP_954657.1
KRT8	NM_001256293.2	c.-47+242G>T		intron_variant	Intron 1 of 8		NP_001243222.1
KRT8	NR_045962.2	n.388G>T		non_coding_transcript_exon_variant	Exon 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT18	ENST00000388835.4	c.300C>A	p.Ser100Arg	missense_variant	Exon 1 of 7	1	NM_000224.3	ENSP00000373487.3

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433002 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 713078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.15e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

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	0.80	D
LIST_S2	Benign	0.46	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	-0.038	T
PROVEAN	Benign	0.21	N;.
REVEL	Benign	0.28
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;