rs2071504

Variant names:

• chr17-7502618-C-T
• rs2071504
• ENST00000674977.2:c.2673C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The ENST00000674977.2(POLR2A):​c.2673C>T​(p.Tyr891Tyr) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.17 (2400 hom., cov: 32)
  • Exomes 𝑓: 0.16 (16047 hom.)
• Consequence: POLR2A ENST00000674977.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.955
• Publications: 22 publications found

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]

POLR2A Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics

ACMG classification

Our verdict: Benign. The variant received -14 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 VariationId is 3056621.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
POLR2A	NM_000937.5	c.2673C>T	p.Tyr891Tyr	synonymous_variant	Exon 16 of 30		NP_000928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR2A	ENST00000674977.2	c.2673C>T	p.Tyr891Tyr	synonymous_variant	Exon 16 of 30			ENSP00000502190.2
POLR2A	ENST00000617998.6	n.3072C>T		non_coding_transcript_exon_variant	Exon 16 of 29	1
POLR2A	ENST00000576114.1	n.139C>T		non_coding_transcript_exon_variant	Exon 2 of 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

GnomAD2 exomes AF: 0.182 AC: 45669 AN: 251344 AF XY: 0.179

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 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

African (AFR) AF: 0.128 AC: 3354 AN: 26292

American (AMR) AF: 0.218 AC: 8140 AN: 37284

Ashkenazi Jewish (ASJ) AF: 0.0938 AC: 1585 AN: 16890

East Asian (EAS) AF: 0.206 AC: 3467 AN: 16804

South Asian (SAS) AF: 0.206 AC: 17134 AN: 83214

European-Finnish (FIN) AF: 0.300 AC: 9778 AN: 32564

Middle Eastern (MID) AF: 0.0789 AC: 353 AN: 4474

European-Non Finnish (NFE) AF: 0.147 AC: 140217 AN: 953660

Other (OTH) AF: 0.160 AC: 7023 AN: 44016

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

African (AFR) AF: 0.138 AC: 5718 AN: 41544

American (AMR) AF: 0.198 AC: 3033 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0960 AC: 333 AN: 3470

East Asian (EAS) AF: 0.206 AC: 1066 AN: 5170

South Asian (SAS) AF: 0.205 AC: 988 AN: 4828

European-Finnish (FIN) AF: 0.311 AC: 3290 AN: 10590

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10327 AN: 68002

Other (OTH) AF: 0.157 AC: 331 AN: 2106

Alfa AF: 0.152 Hom.: 1830

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: no assertion criteria provided

Submissions by phenotype

POLR2A-related disorder Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.95
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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