12-52949556-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_000224.3(KRT18):c.383A>T(p.His128Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,856 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Pathogenic; risk factor no assertion criteria provided P:1 O:2
• 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 Likely_benign. Variant got -4 ACMG points.

• PP5: Variant 12-52949556-A-T is Pathogenic according to our data. Variant chr12-52949556-A-T is described in ClinVar as [Pathogenic, risk_factor]. Clinvar id is 14585.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0725455).. Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT18	NM_000224.3	c.383A>T	p.His128Leu	missense_variant	1/7	ENST00000388835.4
KRT18	NM_199187.2	c.383A>T	p.His128Leu	missense_variant	2/8
KRT8	NM_001256293.2	c.-47+159T>A		intron_variant
KRT8	NR_045962.2	n.305T>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT18	ENST00000388835.4	c.383A>T	p.His128Leu	missense_variant	1/7	1	NM_000224.3	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000633 AC: 158 AN: 249414 Hom.: 3 AF XY: 0.000672 AC XY: 91 AN XY: 135476

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000323 AC: 472 AN: 1461646 Hom.: 3 Cov.: 35 AF XY: 0.000345 AC XY: 251 AN XY: 727136

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000620

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00216 Hom.: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000429 AC: 52

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic; risk factor

Submissions summary: Pathogenic:1 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Cirrhosis, cryptogenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 13, 2003

- -

Cirrhosis, noncryptogenic, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 13, 2003

- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	20
Dann	Benign	0.94
DEOGEN2	Uncertain	0.72	D;.;D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.66	T;T;.
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.86	L;.;L
MutationTaster	Benign	0.0095	A;A;A;A;A
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.014	B;B;B
Vest4		0.50
MVP		1.0
MPC		0.79
ClinPred		0.047	T
GERP RS		1.2
Varity_R		0.29
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs57758506; hg19: chr12-53343340;