4-57010789-G-A

Variant names:

• chr4-57010789-G-A
• rs1718878
• NM_000938.3:c.1590G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The ENST00000314595.6(POLR2B):​c.1590G>A​(p.Ala530Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,604,952 control chromosomes in the GnomAD database, including 100,575 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. Synonymous variant affecting the same amino acid position (i.e. A530A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.37 (10569 hom., cov: 33)
  • Exomes 𝑓: 0.35 (90006 hom.)
• Consequence: POLR2B ENST00000314595.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• Publications: 28 publications found

Genes affected

POLR2B (HGNC:9188): (RNA polymerase II subunit B) This gene encodes the second largest subunit of RNA polymerase II (Pol II), a DNA-dependent RNA polymerase that catalyzes the transcription of DNA into precursors of mRNA, snRNA and microRNA. This subunit and the largest subunit form opposite sides of the center cleft of Pol II. Deletion of the flap loop region of this subunit results in a decrease in the rate of transcriptional elongation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP7: Synonymous conserved (PhyloP=2.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000314595.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2B	NM_000938.3	MANE Select	c.1590G>A	p.Ala530Ala	synonymous	Exon 12 of 25	NP_000929.1
	POLR2B	NM_001303269.2		c.1569G>A	p.Ala523Ala	synonymous	Exon 13 of 26	NP_001290198.1
	POLR2B	NM_001303268.2		c.1365G>A	p.Ala455Ala	synonymous	Exon 11 of 24	NP_001290197.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2B	ENST00000314595.6	TSL:1 MANE Select	c.1590G>A	p.Ala530Ala	synonymous	Exon 12 of 25	ENSP00000312735.5
	POLR2B	ENST00000381227.5	TSL:5	c.1590G>A	p.Ala530Ala	synonymous	Exon 13 of 26	ENSP00000370625.1
	POLR2B	ENST00000441246.6	TSL:2	c.1569G>A	p.Ala523Ala	synonymous	Exon 13 of 26	ENSP00000391452.2

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55910 AN: 151882 Hom.: 10561 Cov.: 33

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.353 AC: 88181 AN: 250148 AF XY: 0.357

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.384

Gnomad EAS exome AF: 0.265

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.349 AC: 506866 AN: 1452952 Hom.: 90006 Cov.: 30 AF XY: 0.352 AC XY: 254198 AN XY: 722908

African (AFR) AF: 0.435 AC: 14452 AN: 33250

American (AMR) AF: 0.301 AC: 13379 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 9934 AN: 26068

East Asian (EAS) AF: 0.262 AC: 10390 AN: 39608

South Asian (SAS) AF: 0.449 AC: 38371 AN: 85462

European-Finnish (FIN) AF: 0.343 AC: 18316 AN: 53386

Middle Eastern (MID) AF: 0.384 AC: 1757 AN: 4578

European-Non Finnish (NFE) AF: 0.343 AC: 379207 AN: 1106084

Other (OTH) AF: 0.351 AC: 21060 AN: 59998

GnomAD4 genome AF: 0.368 AC: 55947 AN: 152000 Hom.: 10569 Cov.: 33 AF XY: 0.368 AC XY: 27342 AN XY: 74278

African (AFR) AF: 0.436 AC: 18077 AN: 41446

American (AMR) AF: 0.319 AC: 4867 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1308 AN: 3468

East Asian (EAS) AF: 0.274 AC: 1420 AN: 5176

South Asian (SAS) AF: 0.464 AC: 2236 AN: 4818

European-Finnish (FIN) AF: 0.338 AC: 3556 AN: 10536

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.343 AC: 23344 AN: 67964

Other (OTH) AF: 0.375 AC: 793 AN: 2112

Alfa AF: 0.349 Hom.: 16832

Bravo AF: 0.365

Asia WGS AF: 0.385 AC: 1339 AN: 3476

EpiCase AF: 0.354

EpiControl AF: 0.341

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.2
DANN	Benign	0.50
PhyloP100		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1718878; hg19: chr4-57876955; COSMIC: COSV58899131;