rs6761

Variant names:

• chr17-7514346-C-T
• rs6761
• ENST00000617998.6:n.6481C>T

Variant summary

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

The ENST00000617998.6(POLR2A):​n.6481C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 388,410 control chromosomes in the GnomAD database, including 63,600 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 0.55 (23751 hom., cov: 32)
  • Exomes 𝑓: 0.57 (39849 hom.)
• Consequence: POLR2A ENST00000617998.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 46 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR2A	NM_000937.5	c.*167C>T		3_prime_UTR_variant	Exon 30 of 30		NP_000928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR2A	ENST00000617998.6	n.6481C>T		non_coding_transcript_exon_variant	Exon 29 of 29	1
POLR2A	ENST00000674977.2	c.*167C>T		downstream_gene_variant				ENSP00000502190.2

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83953 AN: 151960 Hom.: 23760 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.605

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.581

GnomAD4 exome AF: 0.575 AC: 135882 AN: 236332 Hom.: 39849 Cov.: 4 AF XY: 0.566 AC XY: 71206 AN XY: 125804

African (AFR) AF: 0.444 AC: 2662 AN: 6002

American (AMR) AF: 0.606 AC: 4655 AN: 7682

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 2884 AN: 4552

East Asian (EAS) AF: 0.549 AC: 4186 AN: 7624

South Asian (SAS) AF: 0.477 AC: 18934 AN: 39668

European-Finnish (FIN) AF: 0.524 AC: 4884 AN: 9318

Middle Eastern (MID) AF: 0.620 AC: 485 AN: 782

European-Non Finnish (NFE) AF: 0.607 AC: 91217 AN: 150224

Other (OTH) AF: 0.570 AC: 5975 AN: 10480

GnomAD4 genome AF: 0.552 AC: 83958 AN: 152078 Hom.: 23751 Cov.: 32 AF XY: 0.548 AC XY: 40707 AN XY: 74334

African (AFR) AF: 0.443 AC: 18385 AN: 41500

American (AMR) AF: 0.600 AC: 9161 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 2198 AN: 3466

East Asian (EAS) AF: 0.559 AC: 2887 AN: 5166

South Asian (SAS) AF: 0.460 AC: 2221 AN: 4824

European-Finnish (FIN) AF: 0.517 AC: 5471 AN: 10574

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.614 AC: 41734 AN: 67968

Other (OTH) AF: 0.575 AC: 1208 AN: 2100

Alfa AF: 0.595 Hom.: 94593

Bravo AF: 0.554

Asia WGS AF: 0.476 AC: 1658 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.24
DANN	Benign	0.38
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6761; hg19: chr17-7417663; COSMIC: COSV59494619;