12-52949184-C-G

Variant names:

• chr12-52949184-C-G
• rs76301931
• NM_000224.3:c.11C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000224.3(KRT18):​c.11C>G​(p.Thr4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000837 in 1,194,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T4I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630
• Publications: 16 publications found

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]

KRT8 Gene-Disease associations (from GenCC):

• cirrhosis, familial

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067687005).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000224.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT18	NM_000224.3	MANE Select	c.11C>G	p.Thr4Ser	missense	Exon 1 of 7	NP_000215.1	P05783
	KRT18	NM_199187.2		c.11C>G	p.Thr4Ser	missense	Exon 2 of 8	NP_954657.1	P05783
	KRT8	NM_001256293.2		c.-47+531G>C		intron	N/A	NP_001243222.1	P05787-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT18	ENST00000388835.4	TSL:1 MANE Select	c.11C>G	p.Thr4Ser	missense	Exon 1 of 7	ENSP00000373487.3	P05783
	KRT18	ENST00000550600.5	TSL:1	c.11C>G	p.Thr4Ser	missense	Exon 2 of 7	ENSP00000447278.1	F8VZY9
	KRT18	ENST00000872040.1		c.11C>G	p.Thr4Ser	missense	Exon 1 of 7	ENSP00000542099.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246676 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.37e-7 AC: 1 AN: 1194910 Hom.: 0 Cov.: 35 AF XY: 0.00000168 AC XY: 1 AN XY: 595514

African (AFR) AF: 0.00 AC: 0 AN: 27808

American (AMR) AF: 0.00 AC: 0 AN: 39412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21070

East Asian (EAS) AF: 0.00 AC: 0 AN: 29228

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 77842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 908082

Other (OTH) AF: 0.00 AC: 0 AN: 47546

GnomAD4 genome Cov.: 25

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.80
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.063
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.11
Sift	Benign	0.44	T
Sift4G	Benign	0.51	T
Polyphen		0.047	B
Vest4		0.12
MutPred		0.27		Gain of catalytic residue at S7 (P = 0.0267)
MVP		0.62
MPC		0.53
ClinPred		0.073	T
GERP RS		0.94
PromoterAI		-0.062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.37
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs76301931; hg19: chr12-53342968;