4-57017009-G-C

Variant names:

• chr4-57017009-G-C
• rs1718866
• NM_000938.3:c.1956-34G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000938.3(POLR2B):​c.1956-34G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 1,379,928 control chromosomes in the GnomAD database, including 542,127 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 0.89 (60317 hom., cov: 31)
  • Exomes 𝑓: 0.88 (481810 hom.)
• Consequence: POLR2B NM_000938.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000938.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2B	NM_000938.3	MANE Select	c.1956-34G>C		intron	N/A	NP_000929.1	P30876
	POLR2B	NM_001303269.2		c.1935-34G>C		intron	N/A	NP_001290198.1	C9J2Y9
	POLR2B	NM_001303268.2		c.1731-34G>C		intron	N/A	NP_001290197.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2B	ENST00000314595.6	TSL:1 MANE Select	c.1956-34G>C		intron	N/A	ENSP00000312735.5	P30876
	POLR2B	ENST00000381227.5	TSL:5	c.1956-34G>C		intron	N/A	ENSP00000370625.1	P30876
	POLR2B	ENST00000441246.6	TSL:2	c.1935-34G>C		intron	N/A	ENSP00000391452.2	C9J2Y9

Frequencies

GnomAD3 genomes AF: 0.893 AC: 134865 AN: 150948 Hom.: 60273 Cov.: 31

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.764

Gnomad AMR AF: 0.919

Gnomad ASJ AF: 0.897

Gnomad EAS AF: 0.971

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.895

Gnomad MID AF: 0.844

Gnomad NFE AF: 0.872

Gnomad OTH AF: 0.897

GnomAD2 exomes AF: 0.900 AC: 196004 AN: 217856 AF XY: 0.899

Gnomad AFR exome AF: 0.907

Gnomad AMR exome AF: 0.940

Gnomad ASJ exome AF: 0.891

Gnomad EAS exome AF: 0.977

Gnomad FIN exome AF: 0.891

Gnomad NFE exome AF: 0.869

Gnomad OTH exome AF: 0.887

GnomAD4 exome AF: 0.885 AC: 1087482 AN: 1228908 Hom.: 481810 Cov.: 15 AF XY: 0.886 AC XY: 545910 AN XY: 616182

African (AFR) AF: 0.908 AC: 26003 AN: 28638

American (AMR) AF: 0.935 AC: 33885 AN: 36246

Ashkenazi Jewish (ASJ) AF: 0.894 AC: 20140 AN: 22524

East Asian (EAS) AF: 0.978 AC: 34674 AN: 35452

South Asian (SAS) AF: 0.946 AC: 61594 AN: 65108

European-Finnish (FIN) AF: 0.890 AC: 43177 AN: 48512

Middle Eastern (MID) AF: 0.883 AC: 4433 AN: 5020

European-Non Finnish (NFE) AF: 0.874 AC: 818428 AN: 936676

Other (OTH) AF: 0.890 AC: 45148 AN: 50732

GnomAD4 genome AF: 0.894 AC: 134944 AN: 151020 Hom.: 60317 Cov.: 31 AF XY: 0.897 AC XY: 66130 AN XY: 73754

African (AFR) AF: 0.906 AC: 37449 AN: 41342

American (AMR) AF: 0.919 AC: 13918 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.897 AC: 3108 AN: 3466

East Asian (EAS) AF: 0.971 AC: 5024 AN: 5174

South Asian (SAS) AF: 0.947 AC: 4556 AN: 4810

European-Finnish (FIN) AF: 0.895 AC: 8959 AN: 10014

Middle Eastern (MID) AF: 0.846 AC: 242 AN: 286

European-Non Finnish (NFE) AF: 0.872 AC: 59114 AN: 67784

Other (OTH) AF: 0.898 AC: 1879 AN: 2092

Alfa AF: 0.879 Hom.: 10368

Bravo AF: 0.895

Asia WGS AF: 0.938 AC: 3258 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.26
DANN	Benign	0.60
PhyloP100		-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: rs1718866; hg19: chr4-57883175;