12-52949184-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000224.3(KRT18):​c.11C>T​(p.Thr4Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.036 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0630

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14721015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT18	NM_000224.3	c.11C>T	p.Thr4Ile	missense_variant	Exon 1 of 7	ENST00000388835.4	NP_000215.1
KRT18	NM_199187.2	c.11C>T	p.Thr4Ile	missense_variant	Exon 2 of 8		NP_954657.1
KRT8	NM_001256293.2	c.-47+531G>A		intron_variant	Intron 1 of 8		NP_001243222.1
KRT8	NR_045962.2	n.405+272G>A		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT18	ENST00000388835.4	c.11C>T	p.Thr4Ile	missense_variant	Exon 1 of 7	1	NM_000224.3	ENSP00000373487.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1908 AN: 53664 Hom.: 0 Cov.: 25 FAILED QC

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.0342

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.0323

Gnomad SAS AF: 0.0394

Gnomad FIN AF: 0.0669

Gnomad MID AF: 0.0109

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0447

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246676 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134238

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: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00334 AC: 3797 AN: 1136854 Hom.: 0 Cov.: 35 AF XY: 0.00380 AC XY: 2142 AN XY: 564188

Gnomad4 AFR exome AF: 0.00285

Gnomad4 AMR exome AF: 0.000874

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.00160

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.000896

Gnomad4 NFE exome AF: 0.00385

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0356 AC: 1913 AN: 53672 Hom.: 0 Cov.: 25 AF XY: 0.0391 AC XY: 1018 AN XY: 26050

Gnomad4 AFR AF: 0.0331

Gnomad4 AMR AF: 0.0351

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.0335

Gnomad4 SAS AF: 0.0399

Gnomad4 FIN AF: 0.0669

Gnomad4 NFE AF: 0.0327

Gnomad4 OTH AF: 0.0446

Alfa AF: 0.415 Hom.: 0

ExAC AF: 0.0000413 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>T (p.T4I) alteration is located in exon 1 (coding exon 1) of the KRT18 gene. This alteration results from a C to T substitution at nucleotide position 11, causing the threonine (T) at amino acid position 4 to be replaced by an isoleucine (I). 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	Uncertain	0.34
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.63	T;T;.
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.17	B;B;B
Vest4		0.35
MVP		0.62
MPC		0.67
ClinPred		0.24	T
GERP RS		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.55

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: rs76301931; hg19: chr12-53342968; COSMIC: COSV66315748; COSMIC: COSV66315748;