12-52949529-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000224.3(KRT18):c.356A>G(p.Lys119Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12778011).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT18	NM_000224.3	c.356A>G	p.Lys119Arg	missense_variant	1/7	ENST00000388835.4
KRT18	NM_199187.2	c.356A>G	p.Lys119Arg	missense_variant	2/8
KRT8	NM_001256293.2	c.-47+186T>C		intron_variant
KRT8	NR_045962.2	n.332T>C		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT18	ENST00000388835.4	c.356A>G	p.Lys119Arg	missense_variant	1/7	1	NM_000224.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152248 Hom.: 0 Cov.: 35

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000804 AC: 20 AN: 248898 Hom.: 0 AF XY: 0.0000887 AC XY: 12 AN XY: 135336

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1461372 Hom.: 0 Cov.: 35 AF XY: 0.000121 AC XY: 88 AN XY: 726996

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: 0.000149

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152248 Hom.: 0 Cov.: 35 AF XY: 0.0000269 AC XY: 2 AN XY: 74380

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: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000683 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000660 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000178

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

Mar 24, 2023

The c.356A>G (p.K119R) alteration is located in exon 1 (coding exon 1) of the KRT18 gene. This alteration results from a A to G substitution at nucleotide position 356, causing the lysine (K) at amino acid position 119 to be replaced by an arginine (R). 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	0.083
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;T
Eigen	Benign	-0.040
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.43	T;T;.
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.48	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.013	B;B;B
Vest4		0.12
MVP		0.72
MPC		0.62
ClinPred		0.089	T
GERP RS		3.6
Varity_R		0.15
gMVP		0.58

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: rs147945345; hg19: chr12-53343313;