NM_000938.3:c.2335A>G

Variant names:

• chr4-57020910-A-G
• rs370786493
• NM_000938.3:c.2335A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000938.3(POLR2B):​c.2335A>G​(p.Ile779Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000557 in 1,578,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: POLR2B NM_000938.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 6.6178 (above the threshold of 3.09). Trascript score misZ: 6.4623 (above the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.328547).
• BS2: High AC in GnomAd4 at 12 AD gene.

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.2335A>G	p.Ile779Val	missense	Exon 17 of 25	NP_000929.1	P30876
	POLR2B	NM_001303269.2		c.2314A>G	p.Ile772Val	missense	Exon 18 of 26	NP_001290198.1	C9J2Y9
	POLR2B	NM_001303268.2		c.2110A>G	p.Ile704Val	missense	Exon 16 of 24	NP_001290197.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2B	ENST00000314595.6	TSL:1 MANE Select	c.2335A>G	p.Ile779Val	missense	Exon 17 of 25	ENSP00000312735.5	P30876
	POLR2B	ENST00000381227.5	TSL:5	c.2335A>G	p.Ile779Val	missense	Exon 18 of 26	ENSP00000370625.1	P30876
	POLR2B	ENST00000441246.6	TSL:2	c.2314A>G	p.Ile772Val	missense	Exon 18 of 26	ENSP00000391452.2	C9J2Y9

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251326 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000533 AC: 76 AN: 1426264 Hom.: 0 Cov.: 27 AF XY: 0.0000576 AC XY: 41 AN XY: 711860

African (AFR) AF: 0.0000306 AC: 1 AN: 32714

American (AMR) AF: 0.0000224 AC: 1 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 85562

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000639 AC: 69 AN: 1079572

Other (OTH) AF: 0.0000338 AC: 2 AN: 59142

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74366

African (AFR) AF: 0.000169 AC: 7 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.28
Sift	Benign	0.085	T
Sift4G	Benign	0.42	T
Polyphen		0.025	B
Vest4		0.47
MVP		0.52
MPC		1.2
ClinPred		0.14	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.80
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs370786493; hg19: chr4-57887076;