rs2035875

Positions:

• chr12-52902133-A-G
• chr12-52902133-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002273.4(KRT8):​c.325-61T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,036,336 control chromosomes in the GnomAD database, including 148,037 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 0.50 (19383 hom., cov: 30)
  • Exomes 𝑓: 0.53 (128654 hom.)
• Consequence: KRT8 NM_002273.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.625

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT8	NM_002273.4	c.325-61T>C		intron_variant		ENST00000692008.1	NP_002264.1
KRT8	NM_001256282.2	c.409-61T>C		intron_variant			NP_001243211.1
KRT8	NM_001256293.2	c.325-61T>C		intron_variant			NP_001243222.1
KRT8	NR_045962.2	n.776-61T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT8	ENST00000692008.1	c.325-61T>C		intron_variant			NM_002273.4	ENSP00000509398	P2

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76047 AN: 151756 Hom.: 19345 Cov.: 30

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.505

GnomAD4 exome AF: 0.532 AC: 470898 AN: 884462 Hom.: 128654 Cov.: 12 AF XY: 0.538 AC XY: 249361 AN XY: 463164

Gnomad4 AFR exome AF: 0.441

Gnomad4 AMR exome AF: 0.679

Gnomad4 ASJ exome AF: 0.493

Gnomad4 EAS exome AF: 0.637

Gnomad4 SAS exome AF: 0.697

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.508

Gnomad4 OTH exome AF: 0.521

GnomAD4 genome AF: 0.501 AC: 76133 AN: 151874 Hom.: 19383 Cov.: 30 AF XY: 0.504 AC XY: 37399 AN XY: 74192

Gnomad4 AFR AF: 0.442

Gnomad4 AMR AF: 0.570

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.623

Gnomad4 SAS AF: 0.729

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.508

Gnomad4 OTH AF: 0.509

Alfa AF: 0.517 Hom.: 9405

Bravo AF: 0.512

Asia WGS AF: 0.613 AC: 2130 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.1
DANN	Benign	0.70

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: rs2035875; hg19: chr12-53295917; COSMIC: COSV53178462; COSMIC: COSV53178462;