chr12-52950324-C-G

Variant names:

• chr12-52950324-C-G
• rs267607652
• NM_000224.3:c.418-4C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000224.3(KRT18):​c.418-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,608,378 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: KRT18 NM_000224.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001402
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.196
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.418-4C>G		splice_region intron	N/A	NP_000215.1	P05783
	KRT18	NM_199187.2		c.418-4C>G		splice_region intron	N/A	NP_954657.1	P05783

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT18	ENST00000388835.4	TSL:1 MANE Select	c.418-4C>G		splice_region intron	N/A	ENSP00000373487.3	P05783
	KRT18	ENST00000550600.5	TSL:1	c.418-4C>G		splice_region intron	N/A	ENSP00000447278.1	F8VZY9
	KRT18	ENST00000872040.1		c.418-4C>G		splice_region intron	N/A	ENSP00000542099.1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00119 AC: 299 AN: 251408 AF XY: 0.00126

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00114 AC: 1654 AN: 1456036 Hom.: 5 Cov.: 29 AF XY: 0.00119 AC XY: 859 AN XY: 724832

African (AFR) AF: 0.0000900 AC: 3 AN: 33336

American (AMR) AF: 0.00206 AC: 92 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 83 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00214 AC: 184 AN: 86130

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53416

Middle Eastern (MID) AF: 0.00304 AC: 16 AN: 5262

European-Non Finnish (NFE) AF: 0.00106 AC: 1171 AN: 1107212

Other (OTH) AF: 0.00164 AC: 99 AN: 60200

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74492

African (AFR) AF: 0.000192 AC: 8 AN: 41572

American (AMR) AF: 0.000915 AC: 14 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68044

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.000914

EpiCase AF: 0.00185

EpiControl AF: 0.00237

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.9
DANN	Benign	0.68
PhyloP100		-0.20
PromoterAI		-0.0088	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
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: rs267607652; hg19: chr12-53344108;