2-112549250-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_019014.6(POLR1B):c.493-17A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,610,540 control chromosomes in the GnomAD database, including 12,187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2095 hom., cov: 31)
  • Exomes 𝑓: 0.11 (10092 hom.)
• Consequence: POLR1B NM_019014.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.377

Genes affected

POLR1B (HGNC:20454): (RNA polymerase I subunit B) Eukaryotic RNA polymerase I (pol I) is responsible for the transcription of ribosomal RNA (rRNA) genes and production of rRNA, the primary component of ribosomes. Pol I is a multisubunit enzyme composed of 6 to 14 polypeptides, depending on the species. Most of the mass of the pol I complex derives from the 2 largest subunits, Rpa1 and Rpa2 in yeast. POLR1B is homologous to Rpa2 (Seither and Grummt, 1996 [PubMed 8921381]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 2-112549250-A-G is Benign according to our data. Variant chr2-112549250-A-G is described in ClinVar as [Benign]. Clinvar id is 1220927.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR1B	NM_019014.6	c.493-17A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263331.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1B	ENST00000263331.10	c.493-17A>G		splice_polypyrimidine_tract_variant, intron_variant		2	NM_019014.6	P1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22407 AN: 151878 Hom.: 2089 Cov.: 31

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.0824

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.0854

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.137

GnomAD3 exomes AF: 0.139 AC: 34802 AN: 250102 Hom.: 3330 AF XY: 0.132 AC XY: 17792 AN XY: 135300

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.0833

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.135

Gnomad FIN exome AF: 0.0816

Gnomad NFE exome AF: 0.0830

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.105 AC: 153191 AN: 1458544 Hom.: 10092 Cov.: 32 AF XY: 0.104 AC XY: 75829 AN XY: 725778

Gnomad4 AFR exome AF: 0.235

Gnomad4 AMR exome AF: 0.225

Gnomad4 ASJ exome AF: 0.0858

Gnomad4 EAS exome AF: 0.322

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.0825

Gnomad4 NFE exome AF: 0.0873

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.148 AC: 22438 AN: 151996 Hom.: 2095 Cov.: 31 AF XY: 0.149 AC XY: 11052 AN XY: 74296

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.0824

Gnomad4 EAS AF: 0.320

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0854

Gnomad4 NFE AF: 0.0837

Gnomad4 OTH AF: 0.137

Alfa AF: 0.0723 Hom.: 155

Bravo AF: 0.163

Asia WGS AF: 0.241 AC: 839 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	23
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.71		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs62158585; hg19: chr2-113306827; COSMIC: COSV54496051; COSMIC: COSV54496051;