12-52950534-G-T

Variant names:

• chr12-52950534-G-T
• rs2070875
• NM_000224.3:c.500+124G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000224.3(KRT18):​c.500+124G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 839,932 control chromosomes in the GnomAD database, including 12,826 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 0.085 (1658 hom., cov: 32)
  • Exomes 𝑓: 0.092 (11168 hom.)
• Consequence: KRT18 NM_000224.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.894
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT18	NM_000224.3	MANE Select	c.500+124G>T		intron	N/A	NP_000215.1
	KRT18	NM_199187.2		c.500+124G>T		intron	N/A	NP_954657.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT18	ENST00000388835.4	TSL:1 MANE Select	c.500+124G>T		intron	N/A	ENSP00000373487.3
	KRT18	ENST00000550600.5	TSL:1	c.500+124G>T		intron	N/A	ENSP00000447278.1
	KRT18	ENST00000549078.5	TSL:5	n.671G>T		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.0849 AC: 12911 AN: 151998 Hom.: 1648 Cov.: 32

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0900

GnomAD4 exome AF: 0.0925 AC: 63590 AN: 687816 Hom.: 11168 Cov.: 9 AF XY: 0.0927 AC XY: 34217 AN XY: 369252

African (AFR) AF: 0.0972 AC: 1826 AN: 18780

American (AMR) AF: 0.392 AC: 16839 AN: 43008

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 613 AN: 20634

East Asian (EAS) AF: 0.538 AC: 19505 AN: 36232

South Asian (SAS) AF: 0.210 AC: 14529 AN: 69270

European-Finnish (FIN) AF: 0.0336 AC: 1639 AN: 48782

Middle Eastern (MID) AF: 0.0441 AC: 186 AN: 4216

European-Non Finnish (NFE) AF: 0.0138 AC: 5666 AN: 411856

Other (OTH) AF: 0.0795 AC: 2787 AN: 35038

GnomAD4 genome AF: 0.0850 AC: 12937 AN: 152116 Hom.: 1658 Cov.: 32 AF XY: 0.0938 AC XY: 6975 AN XY: 74378

African (AFR) AF: 0.0940 AC: 3901 AN: 41504

American (AMR) AF: 0.227 AC: 3461 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3470

East Asian (EAS) AF: 0.550 AC: 2830 AN: 5142

South Asian (SAS) AF: 0.242 AC: 1163 AN: 4810

European-Finnish (FIN) AF: 0.0353 AC: 375 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0129 AC: 880 AN: 67996

Other (OTH) AF: 0.0975 AC: 206 AN: 2112

Alfa AF: 0.0745 Hom.: 533

Bravo AF: 0.104

Asia WGS AF: 0.341 AC: 1185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.48
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

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: rs2070875; hg19: chr12-53344318; COSMIC: COSV66316083; COSMIC: COSV66316083;