2-112547575-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_019014.6(POLR1B):c.492+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 1,613,218 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0086 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (251 hom.)
• Consequence: POLR1B NM_019014.6 splice_region, intron
• Scores: Splicing: ADA: 0.0003157
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.329

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-112547575-C-T is Benign according to our data. Variant chr2-112547575-C-T is described in ClinVar as [Benign]. Clinvar id is 1261231.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR1B	NM_019014.6	c.492+8C>T		splice_region_variant, intron_variant		ENST00000263331.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1B	ENST00000263331.10	c.492+8C>T		splice_region_variant, intron_variant		2	NM_019014.6	P1

Frequencies

GnomAD3 genomes AF: 0.00861 AC: 1310 AN: 152102 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.0831

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.0125 AC: 3129 AN: 250514 Hom.: 75 AF XY: 0.0122 AC XY: 1646 AN XY: 135414

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00253

Gnomad ASJ exome AF: 0.00678

Gnomad EAS exome AF: 0.0802

Gnomad SAS exome AF: 0.00546

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.00602

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00838 AC: 12240 AN: 1460998 Hom.: 251 Cov.: 33 AF XY: 0.00826 AC XY: 6000 AN XY: 726828

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00258

Gnomad4 ASJ exome AF: 0.00771

Gnomad4 EAS exome AF: 0.0987

Gnomad4 SAS exome AF: 0.00459

Gnomad4 FIN exome AF: 0.0261

Gnomad4 NFE exome AF: 0.00503

Gnomad4 OTH exome AF: 0.00976

GnomAD4 genome AF: 0.00861 AC: 1311 AN: 152220 Hom.: 26 Cov.: 32 AF XY: 0.0100 AC XY: 745 AN XY: 74426

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.0833

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0258

Gnomad4 NFE AF: 0.00616

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00527 Hom.: 4

Bravo AF: 0.00717

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 19, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.7
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.040
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

Publications

LitVar

Other links and lift over

dbSNP: rs78234807; hg19: chr2-113305152; COSMIC: COSV54498993; COSMIC: COSV54498993;