chr12-52949184-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• 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.

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

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>T	p.Thr4Ile	missense	Exon 1 of 7	NP_000215.1	P05783
	KRT18	NM_199187.2		c.11C>T	p.Thr4Ile	missense	Exon 2 of 8	NP_954657.1	P05783
	KRT8	NM_001256293.2		c.-47+531G>A		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>T	p.Thr4Ile	missense	Exon 1 of 7	ENSP00000373487.3	P05783
	KRT18	ENST00000550600.5	TSL:1	c.11C>T	p.Thr4Ile	missense	Exon 2 of 7	ENSP00000447278.1	F8VZY9
	KRT18	ENST00000872040.1		c.11C>T	p.Thr4Ile	missense	Exon 1 of 7	ENSP00000542099.1

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 1908 AN: 53664 Hom.: 0 Cov.: 25

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

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: 0.00000901

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00285 AC: 76 AN: 26690

American (AMR) AF: 0.000874 AC: 34 AN: 38892

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 30 AN: 20564

East Asian (EAS) AF: 0.00160 AC: 45 AN: 28206

South Asian (SAS) AF: 0.00124 AC: 95 AN: 76444

European-Finnish (FIN) AF: 0.000896 AC: 36 AN: 40190

Middle Eastern (MID) AF: 0.00255 AC: 8 AN: 3138

European-Non Finnish (NFE) AF: 0.00385 AC: 3304 AN: 857484

Other (OTH) AF: 0.00374 AC: 169 AN: 45246

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0331 AC: 512 AN: 15462

American (AMR) AF: 0.0351 AC: 191 AN: 5436

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 31 AN: 1158

East Asian (EAS) AF: 0.0335 AC: 60 AN: 1792

South Asian (SAS) AF: 0.0399 AC: 64 AN: 1604

European-Finnish (FIN) AF: 0.0669 AC: 242 AN: 3618

Middle Eastern (MID) AF: 0.0122 AC: 1 AN: 82

European-Non Finnish (NFE) AF: 0.0327 AC: 767 AN: 23436

Other (OTH) AF: 0.0446 AC: 34 AN: 762

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.415 Hom.: 0

ExAC AF: 0.0000413 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.063
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.030	D
Polyphen		0.17	B
Vest4		0.35
MVP		0.62
MPC		0.67
ClinPred		0.24	T
GERP RS		0.94
PromoterAI		-0.067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.55
Mutation Taster		=72/28	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; COSMIC: COSV66315748; COSMIC: COSV66315748;