Genetic Variant NM_002695.5:c.*449A>G (chr19-1088286-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002695.5(POLR2E):c.*449A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 152,196 control chromosomes in the GnomAD database, including 46,368 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 0.78 ( 46332 hom., cov: 32)

Exomes 𝑓: 0.74 ( 36 hom. )

Consequence

POLR2E
NM_002695.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.92

Publications

20 publications found

Variant links:

Genes affected

POLR2E (HGNC:9192): (RNA polymerase II, I and III subunit E) This gene encodes the fifth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. This subunit is shared by the other two DNA-directed RNA polymerases and is present in two-fold molar excess over the other polymerase subunits. An interaction between this subunit and a hepatitis virus transactivating protein has been demonstrated, suggesting that interaction between transcriptional activators and the polymerase can occur through this subunit. A pseudogene is located on chromosome 11. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

POLR2E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002695.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLR2E	NM_002695.5	MANE Select	c.*449A>G	3_prime_UTR	Exon 8 of 8	NP_002686.3
POLR2E	NM_001316323.2		c.*449A>G	3_prime_UTR	Exon 7 of 7	NP_001303252.1	B4DJ89
POLR2E	NM_001316324.2		c.*449A>G	3_prime_UTR	Exon 8 of 8	NP_001303253.1	B4DJ89

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLR2E	ENST00000615234.5	TSL:1 MANE Select	c.*449A>G	3_prime_UTR	Exon 8 of 8	ENSP00000478303.1	P19388
POLR2E	ENST00000885900.1		c.*449A>G	3_prime_UTR	Exon 9 of 9	ENSP00000555959.1
POLR2E	ENST00000885899.1		c.*449A>G	3_prime_UTR	Exon 8 of 8	ENSP00000555958.1

Frequencies

GnomAD3 genomes

AF:

0.777

AC:

118025

AN:

151948

Hom.:

46294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.859

Gnomad AMI

AF:

0.503

Gnomad AMR

AF:

0.803

Gnomad ASJ

AF:

0.725

Gnomad EAS

AF:

0.536

Gnomad SAS

AF:

0.698

Gnomad FIN

AF:

0.742

Gnomad MID

AF:

0.804

Gnomad NFE

AF:

0.757

Gnomad OTH

AF:

0.763

GnomAD4 exome

AF:

0.742

AC:

AN:

128

Hom.:

Cov.:

AF XY:

0.743

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

0.760

AC:

AN:

South Asian (SAS)

AF:

0.750

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.438

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.777

AC:

118113

AN:

152068

Hom.:

46332

Cov.:

AF XY:

0.773

AC XY:

57482

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.859

AC:

35659

AN:

41504

American (AMR)

AF:

0.803

AC:

12275

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.725

AC:

2516

AN:

3472

East Asian (EAS)

AF:

0.534

AC:

2746

AN:

5140

South Asian (SAS)

AF:

0.698

AC:

3355

AN:

4806

European-Finnish (FIN)

AF:

0.742

AC:

7853

AN:

10582

Middle Eastern (MID)

AF:

0.813

AC:

239

AN:

294

European-Non Finnish (NFE)

AF:

0.757

AC:

51422

AN:

67962

Other (OTH)

AF:

0.754

AC:

1591

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1316

2633

3949

5266

6582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.763

Hom.:

142556

Bravo

AF:

0.785

Asia WGS

AF:

0.623

AC:

2168

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.30

(source)

DANN

Benign

0.12

PhyloP100

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over