NM_000224.3:c.657+140C>A

Variant names:

• chr12-52951046-C-A
• rs2070876
• NM_000224.3:c.657+140C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000224.3(KRT18):​c.657+140C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000164 in 609,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: KRT18 NM_000224.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.74
• Publications: 0 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]

KRT18 Gene-Disease associations (from GenCC):

• cirrhosis, familial

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000164 AC: 1 AN: 609994 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 316384

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

African (AFR) AF: 0.00 AC: 0 AN: 15618

American (AMR) AF: 0.00 AC: 0 AN: 21688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15330

East Asian (EAS) AF: 0.00 AC: 0 AN: 31966

South Asian (SAS) AF: 0.00 AC: 0 AN: 49770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2336

European-Non Finnish (NFE) AF: 0.00000243 AC: 1 AN: 411984

Other (OTH) AF: 0.00 AC: 0 AN: 31434

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.36
DANN	Benign	0.60
PhyloP100		-1.7

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

Other links and lift over

dbSNP: rs2070876; hg19: chr12-53344830;