Genetic Variant POLR2A:p.Arg16Ser (chr17-7484810-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000937.5(POLR2A):c.46C>A(p.Arg16Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,453,352 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: 0.0000028 ( 0 hom. )

Consequence

POLR2A
NM_000937.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.50

Publications

0 publications found

Variant links:

Genes affected

POLR2A (HGNC:9187): (RNA polymerase II subunit A) This gene encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains a carboxy terminal domain composed of heptapeptide repeats that are essential for polymerase activity. These repeats contain serine and threonine residues that are phosphorylated in actively transcribing RNA polymerase. In addition, this subunit, in combination with several other polymerase subunits, forms the DNA binding domain of the polymerase, a groove in which the DNA template is transcribed into RNA. [provided by RefSeq, Jul 2008]

POLR2A Gene-Disease associations (from GenCC):

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Broad Center for Mendelian Genomics, ClinGen

POLR2A links:

ENSG00000306936 (HGNC:):

ENSG00000306936 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000937.5. 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
	POLR2A	NM_000937.5	MANE Select	c.46C>A	p.Arg16Ser	missense	Exon 1 of 30	NP_000928.1	A0AAG2TJB2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLR2A	ENST00000674977.2		c.46C>A	p.Arg16Ser	missense	Exon 1 of 30	ENSP00000502190.2	A0A6Q8PGB0
POLR2A	ENST00000572844.1	TSL:1	n.191C>A		non_coding_transcript_exon	Exon 1 of 10
POLR2A	ENST00000617998.6	TSL:1	n.445C>A		non_coding_transcript_exon	Exon 1 of 29

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000438

AC:

AN:

228158

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000997

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1453352

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33340

American (AMR)

AF:

0.00

AC:

AN:

43598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

39364

South Asian (SAS)

AF:

0.00

AC:

AN:

84530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1108772

Other (OTH)

AF:

0.00

AC:

AN:

60090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.8

PhyloP100

5.5

PrimateAI

Pathogenic

0.88

Sift4G

Benign

0.063

Vest4

0.63

MVP

0.82

ClinPred

0.98

GERP RS

5.8

PromoterAI

-0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

gMVP

0.70

Mutation Taster

=10/90

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over