12-52898452-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002273.4(KRT8):c.1261+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,612,252 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (46 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (43 hom.)
• Consequence: KRT8 NM_002273.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.910

Genes affected

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-52898452-G-A is Benign according to our data. Variant chr12-52898452-G-A is described in ClinVar as [Benign]. Clinvar id is 787398.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2045/152100) while in subpopulation AFR AF= 0.0459 (1904/41510). AF 95% confidence interval is 0.0442. There are 46 homozygotes in gnomad4. There are 1002 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 45 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT8	NM_002273.4	c.1261+9C>T		intron_variant		ENST00000692008.1
KRT8	NM_001256282.2	c.1345+9C>T		intron_variant
KRT8	NM_001256293.2	c.1261+9C>T		intron_variant
KRT8	NR_045962.2	n.1712+9C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT8	ENST00000692008.1	c.1261+9C>T		intron_variant			NM_002273.4	P2

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2035 AN: 151986 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00715

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.00328 AC: 816 AN: 248648 Hom.: 21 AF XY: 0.00247 AC XY: 333 AN XY: 134658

Gnomad AFR exome AF: 0.0461

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000889

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00138 AC: 2018 AN: 1460152 Hom.: 43 Cov.: 32 AF XY: 0.00122 AC XY: 883 AN XY: 726268

Gnomad4 AFR exome AF: 0.0468

Gnomad4 AMR exome AF: 0.00265

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.0134 AC: 2045 AN: 152100 Hom.: 46 Cov.: 33 AF XY: 0.0135 AC XY: 1002 AN XY: 74344

Gnomad4 AFR AF: 0.0459

Gnomad4 AMR AF: 0.00714

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00760

Alfa AF: 0.00612 Hom.: 12

Bravo AF: 0.0152

Asia WGS AF: 0.00202 AC: 7 AN: 3474

EpiCase AF: 0.000218

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.6
Dann	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs185715618; hg19: chr12-53292236;