chr17-7492230-A-G

Variant names:

• chr17-7492230-A-G
• rs7217258
• NM_000937.5:c.94-3711A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000937.5(POLR2A):​c.94-3711A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 152,068 control chromosomes in the GnomAD database, including 6,366 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 0.27 (6366 hom., cov: 32)
• Consequence: POLR2A NM_000937.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.568
• Publications: 10 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: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2A	NM_000937.5	MANE Select	c.94-3711A>G		intron	N/A	NP_000928.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR2A	ENST00000674977.2		c.94-3711A>G		intron	N/A	ENSP00000502190.2
	POLR2A	ENST00000572844.1	TSL:1	n.239-3711A>G		intron	N/A
	POLR2A	ENST00000617998.6	TSL:1	n.493-3711A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41601 AN: 151950 Hom.: 6357 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.274

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.274 AC: 41629 AN: 152068 Hom.: 6366 Cov.: 32 AF XY: 0.280 AC XY: 20824 AN XY: 74332

African (AFR) AF: 0.225 AC: 9330 AN: 41504

American (AMR) AF: 0.363 AC: 5543 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 958 AN: 3468

East Asian (EAS) AF: 0.694 AC: 3590 AN: 5174

South Asian (SAS) AF: 0.375 AC: 1806 AN: 4818

European-Finnish (FIN) AF: 0.247 AC: 2609 AN: 10556

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16976 AN: 67972

Other (OTH) AF: 0.272 AC: 574 AN: 2110

Alfa AF: 0.263 Hom.: 9255

Bravo AF: 0.281

Asia WGS AF: 0.468 AC: 1630 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.0
DANN	Benign	0.72
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs7217258; hg19: chr17-7395549; COSMIC: COSV59490614;