Genetic Variant NM_000224.3:c.657+140C>T (chr12-52951046-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000224.3(KRT18):c.657+140C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 761,054 control chromosomes in the GnomAD database, including 57,581 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.38 ( 11592 hom., cov: 32)

Exomes 𝑓: 0.38 ( 45989 hom. )

Consequence

KRT18
NM_000224.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.74

Publications

12 publications found

Variant links:

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]

KRT18 Gene-Disease associations (from GenCC):

cirrhosis, familial
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

KRT18 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT18	NM_000224.3 link	c.657+140C>T		intron_variant	Intron 3 of 6	ENST00000388835.4	NP_000215.1	P05783A0A024RAY2
KRT18	NM_199187.2 link	c.657+140C>T		intron_variant	Intron 4 of 7		NP_954657.1	P05783A0A024RAY2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT18	ENST00000388835.4 link	c.657+140C>T		intron_variant	Intron 3 of 6	1	NM_000224.3	ENSP00000373487.3		P05783

Frequencies

GnomAD3 genomes

AF:

0.384

AC:

58402

AN:

151908

Hom.:

11586

Cov.:

show subpopulations

Gnomad AFR

AF:

0.379

Gnomad AMI

AF:

0.356

Gnomad AMR

AF:

0.466

Gnomad ASJ

AF:

0.416

Gnomad EAS

AF:

0.584

Gnomad SAS

AF:

0.421

Gnomad FIN

AF:

0.271

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.367

Gnomad OTH

AF:

0.401

GnomAD4 exome

AF:

0.379

AC:

230707

AN:

609028

Hom.:

45989

AF XY:

0.380

AC XY:

119918

AN XY:

315900

show subpopulations

African (AFR)

AF:

0.370

AC:

5766

AN:

15600

American (AMR)

AF:

0.522

AC:

11323

AN:

21672

Ashkenazi Jewish (ASJ)

AF:

0.421

AC:

6451

AN:

15306

East Asian (EAS)

AF:

0.558

AC:

17836

AN:

31946

South Asian (SAS)

AF:

0.399

AC:

19832

AN:

49734

European-Finnish (FIN)

AF:

0.292

AC:

8698

AN:

29838

Middle Eastern (MID)

AF:

0.373

AC:

872

AN:

2336

European-Non Finnish (NFE)

AF:

0.359

AC:

147819

AN:

411200

Other (OTH)

AF:

0.386

AC:

12110

AN:

31396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

7522

15045

22567

30090

37612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2478

4956

7434

9912

12390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.384

AC:

58439

AN:

152026

Hom.:

11592

Cov.:

AF XY:

0.385

AC XY:

28640

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.379

AC:

15691

AN:

41438

American (AMR)

AF:

0.466

AC:

7127

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.416

AC:

1443

AN:

3466

East Asian (EAS)

AF:

0.583

AC:

3014

AN:

5174

South Asian (SAS)

AF:

0.420

AC:

2026

AN:

4820

European-Finnish (FIN)

AF:

0.271

AC:

2867

AN:

10576

Middle Eastern (MID)

AF:

0.432

AC:

127

AN:

294

European-Non Finnish (NFE)

AF:

0.367

AC:

24963

AN:

67954

Other (OTH)

AF:

0.406

AC:

856

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1850

3699

5549

7398

9248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

552

1104

1656

2208

2760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.382

Hom.:

50165

Bravo

AF:

0.404

Asia WGS

AF:

0.477

AC:

1660

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.5

(source)

DANN

Benign

0.70

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over