19-1090804-A-G

Variant summary

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

The NM_002695.5(POLR2E):c.429+104T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 972,496 control chromosomes in the GnomAD database, including 275,264 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 0.77 (45630 hom., cov: 32)
  • Exomes 𝑓: 0.74 (229634 hom.)
• Consequence: POLR2E NM_002695.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.24

Genes affected

POLR2E (HGNC:9192): (RNA polymerase II, I and III subunit E) This gene encodes the fifth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. This subunit is shared by the other two DNA-directed RNA polymerases and is present in two-fold molar excess over the other polymerase subunits. An interaction between this subunit and a hepatitis virus transactivating protein has been demonstrated, suggesting that interaction between transcriptional activators and the polymerase can occur through this subunit. A pseudogene is located on chromosome 11. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR2E	NM_002695.5	c.429+104T>C		intron_variant		ENST00000615234.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR2E	ENST00000615234.5	c.429+104T>C		intron_variant		1	NM_002695.5	P1

Frequencies

GnomAD3 genomes AF: 0.770 AC: 117092 AN: 151974 Hom.: 45591 Cov.: 32

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.752

GnomAD4 exome AF: 0.744 AC: 610676 AN: 820404 Hom.: 229634 AF XY: 0.744 AC XY: 312426 AN XY: 419908

Gnomad4 AFR exome AF: 0.862

Gnomad4 AMR exome AF: 0.841

Gnomad4 ASJ exome AF: 0.719

Gnomad4 EAS exome AF: 0.482

Gnomad4 SAS exome AF: 0.733

Gnomad4 FIN exome AF: 0.728

Gnomad4 NFE exome AF: 0.753

Gnomad4 OTH exome AF: 0.744

GnomAD4 genome AF: 0.770 AC: 117179 AN: 152092 Hom.: 45630 Cov.: 32 AF XY: 0.767 AC XY: 57002 AN XY: 74348

Gnomad4 AFR AF: 0.857

Gnomad4 AMR AF: 0.795

Gnomad4 ASJ AF: 0.723

Gnomad4 EAS AF: 0.530

Gnomad4 SAS AF: 0.700

Gnomad4 FIN AF: 0.734

Gnomad4 NFE AF: 0.748

Gnomad4 OTH AF: 0.744

Alfa AF: 0.760 Hom.: 22606

Bravo AF: 0.779

Asia WGS AF: 0.624 AC: 2172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.29
Dann	Benign	0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3787016; hg19: chr19-1090803; COSMIC: COSV53123968; COSMIC: COSV53123968;