rs2071504

chr17-7502618-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000937.5(POLR2A):c.2673C>T(p.Tyr891=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,367,392 control chromosomes in the GnomAD database, including 18,447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2400 hom., cov: 32)
  • Exomes 𝑓: 0.16 (16047 hom.)
• Consequence: POLR2A NM_000937.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.955

Genes affected

POLR2A (HGNC:9187): (RNA polymerase II subunit A) This gene encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains a carboxy terminal domain composed of heptapeptide repeats that are essential for polymerase activity. These repeats contain serine and threonine residues that are phosphorylated in actively transcribing RNA polymerase. In addition, this subunit, in combination with several other polymerase subunits, forms the DNA binding domain of the polymerase, a groove in which the DNA template is transcribed into RNA. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 17-7502618-C-T is Benign according to our data. Variant chr17-7502618-C-T is described in ClinVar as [Benign]. Clinvar id is 3056621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.955 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR2A	NM_000937.5	c.2673C>T	p.Tyr891=	synonymous_variant	16/30	ENST00000643490.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR2A	ENST00000674977.2	c.2673C>T	p.Tyr891=	synonymous_variant	16/30			P1
POLR2A	ENST00000617998.6	n.3072C>T		non_coding_transcript_exon_variant	16/29	1
POLR2A	ENST00000576114.1	n.139C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25210 AN: 152074 Hom.: 2384 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.0960

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.182 AC: 45669 AN: 251344 Hom.: 4602 AF XY: 0.179 AC XY: 24375 AN XY: 135880

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.0964

Gnomad EAS exome AF: 0.202

Gnomad SAS exome AF: 0.211

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.157 AC: 191051 AN: 1215198 Hom.: 16047 Cov.: 32 AF XY: 0.158 AC XY: 95438 AN XY: 602260

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.0938

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.147

Gnomad4 OTH exome AF: 0.160

GnomAD4 genome AF: 0.166 AC: 25243 AN: 152194 Hom.: 2400 Cov.: 32 AF XY: 0.175 AC XY: 12985 AN XY: 74388

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.0960

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.157

Alfa AF: 0.152 Hom.: 1390

Bravo AF: 0.154

Asia WGS AF: 0.266 AC: 924 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.133

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

POLR2A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.23
Dann	Benign	0.70
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

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: rs2071504; hg19: chr17-7405937; COSMIC: COSV59489442;