rs74379840

Variant names:

• chr12-52949256-C-A
• rs74379840
• NM_000224.3:c.83C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-52949256-C-A
• chr12-52949256-C-G
• chr12-52949256-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000224.3(KRT18):​c.83C>A​(p.Pro28Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P28L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (1 hom., cov: 37)
  • Exomes 𝑓: 0.0044 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT18 NM_000224.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• 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 0 ACMG points.

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.83C>A	p.Pro28Gln	missense	Exon 1 of 7	NP_000215.1	P05783
	KRT18	NM_199187.2		c.83C>A	p.Pro28Gln	missense	Exon 2 of 8	NP_954657.1	P05783
	KRT8	NM_001256293.2		c.-47+459G>T		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.83C>A	p.Pro28Gln	missense	Exon 1 of 7	ENSP00000373487.3	P05783
	KRT18	ENST00000550600.5	TSL:1	c.83C>A	p.Pro28Gln	missense	Exon 2 of 7	ENSP00000447278.1	F8VZY9
	KRT18	ENST00000872040.1		c.83C>A	p.Pro28Gln	missense	Exon 1 of 7	ENSP00000542099.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 23329 AN: 76096 Hom.: 1 Cov.: 37

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.277

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00437 AC: 5508 AN: 1259582 Hom.: 3 Cov.: 37 AF XY: 0.00640 AC XY: 3971 AN XY: 620856

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

African (AFR) AF: 0.00484 AC: 140 AN: 28934

American (AMR) AF: 0.00379 AC: 142 AN: 37450

Ashkenazi Jewish (ASJ) AF: 0.00322 AC: 69 AN: 21444

East Asian (EAS) AF: 0.00576 AC: 173 AN: 30048

South Asian (SAS) AF: 0.00129 AC: 97 AN: 75384

European-Finnish (FIN) AF: 0.00552 AC: 210 AN: 38020

Middle Eastern (MID) AF: 0.00584 AC: 20 AN: 3426

European-Non Finnish (NFE) AF: 0.00445 AC: 4333 AN: 974786

Other (OTH) AF: 0.00647 AC: 324 AN: 50090

⚠️ 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: 0.307 AC: 23353 AN: 76154 Hom.: 1 Cov.: 37 AF XY: 0.309 AC XY: 11589 AN XY: 37452

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

African (AFR) AF: 0.289 AC: 6152 AN: 21284

American (AMR) AF: 0.299 AC: 2344 AN: 7832

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 508 AN: 1588

East Asian (EAS) AF: 0.255 AC: 651 AN: 2552

South Asian (SAS) AF: 0.246 AC: 568 AN: 2306

European-Finnish (FIN) AF: 0.342 AC: 1957 AN: 5724

Middle Eastern (MID) AF: 0.294 AC: 37 AN: 126

European-Non Finnish (NFE) AF: 0.321 AC: 10646 AN: 33174

Other (OTH) AF: 0.279 AC: 301 AN: 1080

⚠️ 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: 0.428 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.14	T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.33
Sift	Benign	0.098	T
Sift4G	Benign	0.22	T
Polyphen		0.98	D
Vest4		0.42
MVP		0.61
MPC		1.0
ClinPred		0.57	D
GERP RS		2.8
PromoterAI		0.055	Neutral
Varity_R		0.089
gMVP		0.59
Mutation Taster		=95/5	polymorphism

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: rs74379840; hg19: chr12-53343040; COSMIC: COSV66315760; COSMIC: COSV66315760;