chr17-7484849-G-C

Variant names:

• chr17-7484849-G-C
• NM_000937.5:c.85G>C

Variant summary

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

The NM_000937.5(POLR2A):​c.85G>C​(p.Asp29His) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,440,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLR2A NM_000937.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91
• Publications: 0 publications found

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

ENSG00000306936 (HGNC:):

ACMG classification

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.85G>C	p.Asp29His	missense	Exon 1 of 30	NP_000928.1	A0AAG2TJB2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2A	ENST00000674977.2		c.85G>C	p.Asp29His	missense	Exon 1 of 30	ENSP00000502190.2	A0A6Q8PGB0
	POLR2A	ENST00000572844.1	TSL:1	n.230G>C		non_coding_transcript_exon	Exon 1 of 10
	POLR2A	ENST00000617998.6	TSL:1	n.484G>C		non_coding_transcript_exon	Exon 1 of 29

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440834 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 715842

African (AFR) AF: 0.00 AC: 0 AN: 33188

American (AMR) AF: 0.00 AC: 0 AN: 42502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25514

East Asian (EAS) AF: 0.00 AC: 0 AN: 39172

South Asian (SAS) AF: 0.00 AC: 0 AN: 83652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099746

Other (OTH) AF: 0.00 AC: 0 AN: 59696

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Benign	0.42	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.9
PrimateAI	Pathogenic	0.80	D
Sift4G	Uncertain	0.057	T
Vest4		0.68
MutPred		0.42		Gain of MoRF binding (P = 0.0476)
MVP		0.92
ClinPred		0.99	D
GERP RS		5.8
PromoterAI		-0.080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.67

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

Other links and lift over

hg19: chr17-7388168;