Variant chr4-57023570-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000938.3(POLR2B):c.2756G>A(p.Cys919Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

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: 8.00

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:

POLR2B (HGNC:):

POLR2B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR2B	NM_000938.3 linkuse as main transcript	c.2756G>A	p.Cys919Tyr	missense_variant	19/25	ENST00000314595.6	NP_000929.1	P30876B4DH29
POLR2B	NM_001303269.2 linkuse as main transcript	c.2735G>A	p.Cys912Tyr	missense_variant	20/26		NP_001290198.1	P30876C9J2Y9B4DHJ3B4DH29
POLR2B	NM_001303268.2 linkuse as main transcript	c.2531G>A	p.Cys844Tyr	missense_variant	18/24		NP_001290197.1	P30876B4DH29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR2B	ENST00000314595.6 linkuse as main transcript	c.2756G>A	p.Cys919Tyr	missense_variant	19/25	1	NM_000938.3	ENSP00000312735.5		P30876

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250906

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461660

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Dec 15, 2022

The c.2756G>A (p.C919Y) alteration is located in exon 19 (coding exon 19) of the POLR2B gene. This alteration results from a G to A substitution at nucleotide position 2756, causing the cysteine (C) at amino acid position 919 to be replaced by a tyrosine (Y). 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

0.99

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.;.;D;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

.;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.72

D;D;D;D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.43

N;.;.;N;.

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-2.5

D;.;D;D;.

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;.;D;D;.

Sift4G

Uncertain

0.038

D;.;D;D;.

Polyphen

0.77

P;.;.;P;.

Vest4

0.81

MutPred

0.56

Loss of methylation at K920 (P = 0.0144);.;.;Loss of methylation at K920 (P = 0.0144);.;

MVP

0.88

MPC

2.8

ClinPred

0.93

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.99

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

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