12-52949447-G-C

Variant names:

• chr12-52949447-G-C
• rs1434610693
• NM_000224.3:c.274G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PP3_Strong BP6_Moderate

The NM_000224.3(KRT18):​c.274G>C​(p.Ala92Pro) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.47 (0 hom., cov: 38)
  • Exomes 𝑓: 0.00038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 5.62
• Publications: 10 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• BP6: Variant 12-52949447-G-C is Benign according to our data. Variant chr12-52949447-G-C is described in ClinVar as Benign. ClinVar VariationId is 1205843.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT18	NM_000224.3	c.274G>C	p.Ala92Pro	missense_variant	Exon 1 of 7	ENST00000388835.4	NP_000215.1
KRT18	NM_199187.2	c.274G>C	p.Ala92Pro	missense_variant	Exon 2 of 8		NP_954657.1
KRT8	NM_001256293.2	c.-47+268C>G		intron_variant	Intron 1 of 8		NP_001243222.1
KRT8	NR_045962.2	n.405+9C>G		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT18	ENST00000388835.4	c.274G>C	p.Ala92Pro	missense_variant	Exon 1 of 7	1	NM_000224.3	ENSP00000373487.3

Frequencies

GnomAD3 genomes AF: 0.466 AC: 40011 AN: 85882 Hom.: 0 Cov.: 38

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.456

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000383 AC: 508 AN: 1328096 Hom.: 0 Cov.: 36 AF XY: 0.000410 AC XY: 270 AN XY: 659320

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

African (AFR) AF: 0.000231 AC: 7 AN: 30284

American (AMR) AF: 0.000195 AC: 8 AN: 40962

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 5 AN: 21784

East Asian (EAS) AF: 0.000848 AC: 25 AN: 29494

South Asian (SAS) AF: 0.000230 AC: 19 AN: 82656

European-Finnish (FIN) AF: 0.00278 AC: 111 AN: 39952

Middle Eastern (MID) AF: 0.0272 AC: 116 AN: 4262

European-Non Finnish (NFE) AF: 0.000176 AC: 181 AN: 1026418

Other (OTH) AF: 0.000689 AC: 36 AN: 52284

⚠️ 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;InbreedingCoeff AF: 0.466 AC: 40039 AN: 85958 Hom.: 0 Cov.: 38 AF XY: 0.465 AC XY: 19905 AN XY: 42852

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

African (AFR) AF: 0.451 AC: 10626 AN: 23554

American (AMR) AF: 0.472 AC: 4028 AN: 8542

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 951 AN: 1986

East Asian (EAS) AF: 0.454 AC: 1204 AN: 2654

South Asian (SAS) AF: 0.459 AC: 1168 AN: 2544

European-Finnish (FIN) AF: 0.474 AC: 3151 AN: 6654

Middle Eastern (MID) AF: 0.467 AC: 56 AN: 120

European-Non Finnish (NFE) AF: 0.473 AC: 18070 AN: 38214

Other (OTH) AF: 0.456 AC: 525 AN: 1152

⚠️ 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: 0.438 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;.
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;H
PhyloP100		5.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.87
MVP		0.96
MPC		1.7
ClinPred		1.0	D
GERP RS		3.8
PromoterAI		0.012	Neutral
Varity_R		0.97
gMVP		0.98
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1434610693; hg19: chr12-53343231; COSMIC: COSV66315787; COSMIC: COSV66315787;