12-52949347-G-GA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000224.3(KRT18):c.174_175insA(p.Gly59ArgfsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.36 (0 hom., cov: 37)
  • Exomes 𝑓: 0.000073 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT18 NM_000224.3 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.45

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP6: Variant 12-52949347-G-GA is Benign according to our data. Variant chr12-52949347-G-GA is described in ClinVar as [Benign]. Clinvar id is 1301593.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT18	NM_000224.3	c.174_175insA	p.Gly59ArgfsTer97	frameshift_variant	1/7	ENST00000388835.4
KRT18	NM_199187.2	c.174_175insA	p.Gly59ArgfsTer97	frameshift_variant	2/8
KRT8	NM_001256293.2	c.-47+367_-47+368insT		intron_variant
KRT8	NR_045962.2	n.405+108_405+109insT		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT18	ENST00000388835.4	c.174_175insA	p.Gly59ArgfsTer97	frameshift_variant	1/7	1	NM_000224.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 27412 AN: 75740 Hom.: 0 Cov.: 37 FAILED QC

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.148

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.312

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000734 AC: 104 AN: 1416492 Hom.: 0 Cov.: 36 AF XY: 0.0000668 AC XY: 47 AN XY: 703460

Gnomad4 AFR exome AF: 0.000123

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.000202

Gnomad4 EAS exome AF: 0.0000828

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.000684

Gnomad4 NFE exome AF: 0.0000377

Gnomad4 OTH exome AF: 0.000104

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.362 AC: 27431 AN: 75794 Hom.: 0 Cov.: 37 AF XY: 0.364 AC XY: 13880 AN XY: 38160

Gnomad4 AFR AF: 0.355

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.395

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.336

Gnomad4 NFE AF: 0.385

Gnomad4 OTH AF: 0.314

Alfa AF: 0.108 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Jan 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1304463116; hg19: chr12-53343131;