rs9646411

Variant names:

• chr17-7495590-C-T
• rs9646411
• ENST00000674977.2:c.94-351C>T

Variant summary

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

The ENST00000674977.2(POLR2A):​c.94-351C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 151,830 control chromosomes in the GnomAD database, including 2,640 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 0.18 (2640 hom., cov: 31)
• Consequence: POLR2A ENST00000674977.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.514
• Publications: 9 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=-0.75).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR2A	NM_000937.5	c.94-351C>T		intron_variant	Intron 1 of 29		NP_000928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR2A	ENST00000674977.2	c.94-351C>T		intron_variant	Intron 1 of 29			ENSP00000502190.2
POLR2A	ENST00000572844.1	n.239-351C>T		intron_variant	Intron 1 of 9	1
POLR2A	ENST00000617998.6	n.493-351C>T		intron_variant	Intron 1 of 28	1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27321 AN: 151712 Hom.: 2644 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.0311

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.197

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

GnomAD4 genome AF: 0.180 AC: 27322 AN: 151830 Hom.: 2640 Cov.: 31 AF XY: 0.177 AC XY: 13111 AN XY: 74192

African (AFR) AF: 0.159 AC: 6579 AN: 41368

American (AMR) AF: 0.145 AC: 2206 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3462

East Asian (EAS) AF: 0.0312 AC: 161 AN: 5164

South Asian (SAS) AF: 0.278 AC: 1339 AN: 4812

European-Finnish (FIN) AF: 0.140 AC: 1477 AN: 10538

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14032 AN: 67938

Other (OTH) AF: 0.195 AC: 412 AN: 2110

Alfa AF: 0.191 Hom.: 401

Bravo AF: 0.180

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.4
DANN	Benign	0.76
PhyloP100		-0.51
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: rs9646411; hg19: chr17-7398909;