Variant 4-56994759-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000938.3(POLR2B):c.469C>T(p.Arg157Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

POLR2B
NM_000938.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.87

Variant links:

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]

POLR2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR2B	NM_000938.3 linkuse as main transcript	c.469C>T	p.Arg157Trp	missense_variant	5/25	ENST00000314595.6	NP_000929.1	P30876B4DH29
POLR2B	NM_001303269.2 linkuse as main transcript	c.448C>T	p.Arg150Trp	missense_variant	6/26		NP_001290198.1	P30876C9J2Y9B4DHJ3B4DH29
POLR2B	NM_001303268.2 linkuse as main transcript	c.244C>T	p.Arg82Trp	missense_variant	4/24		NP_001290197.1	P30876B4DH29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
POLR2B	ENST00000314595.6 linkuse as main transcript	c.469C>T	p.Arg157Trp	missense_variant	5/25	1	NM_000938.3	ENSP00000312735.5	P30876
POLR2B	ENST00000381227.5 linkuse as main transcript	c.469C>T	p.Arg157Trp	missense_variant	6/26	5		ENSP00000370625.1	P30876
POLR2B	ENST00000441246.6 linkuse as main transcript	c.448C>T	p.Arg150Trp	missense_variant	6/26	2		ENSP00000391452.2	C9J2Y9
POLR2B	ENST00000431623.6 linkuse as main transcript	c.148C>T	p.Arg50Trp	missense_variant	4/24	2		ENSP00000391096.3	C9J4M6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460810

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726814

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2024

The c.469C>T (p.R157W) alteration is located in exon 5 (coding exon 5) of the POLR2B gene. This alteration results from a C to T substitution at nucleotide position 469, causing the arginine (R) at amino acid position 157 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.;.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.8

H;.;.;H;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.7

D;.;D;D;.

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;.;D;D;.

Sift4G

Pathogenic

0.0

D;.;D;D;.

Polyphen

1.0

D;.;.;D;.

Vest4

0.83

MutPred

0.84

Loss of sheet (P = 0.1158);.;.;Loss of sheet (P = 0.1158);.;

MVP

0.71

MPC

2.4

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over