chr2-112551896-C-T

Position:

• chr2-112551896-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_019014.6(POLR1B):​c.884C>T​(p.Ser295Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,613,374 control chromosomes in the GnomAD database, including 255,197 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.51 (20439 hom., cov: 32)
  • Exomes 𝑓: 0.56 (234758 hom.)
• Consequence: POLR1B NM_019014.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0840

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]

POLR1B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), POLR1B. . Gene score misZ 2.9739 (greater than the threshold 3.09). Trascript score misZ 4.7393 (greater than threshold 3.09). GenCC has associacion of gene with Treacher-Collins syndrome, Treacher Collins syndrome 4.
• BP4: Computational evidence support a benign effect (MetaRNN=3.0312503E-6).
• BP6: Variant 2-112551896-C-T is Benign according to our data. Variant chr2-112551896-C-T is described in ClinVar as [Benign]. Clinvar id is 1260138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1B	NM_019014.6	c.884C>T	p.Ser295Leu	missense_variant	6/15	ENST00000263331.10	NP_061887.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1B	ENST00000263331.10	c.884C>T	p.Ser295Leu	missense_variant	6/15	2	NM_019014.6	ENSP00000263331.5

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77666 AN: 151834 Hom.: 20427 Cov.: 32

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.554

GnomAD3 exomes AF: 0.522 AC: 131281 AN: 251460 Hom.: 35301 AF XY: 0.528 AC XY: 71818 AN XY: 135910

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.461

Gnomad ASJ exome AF: 0.622

Gnomad EAS exome AF: 0.350

Gnomad SAS exome AF: 0.499

Gnomad FIN exome AF: 0.483

Gnomad NFE exome AF: 0.587

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.563 AC: 822793 AN: 1461422 Hom.: 234758 Cov.: 45 AF XY: 0.563 AC XY: 409138 AN XY: 727022

Gnomad4 AFR exome AF: 0.412

Gnomad4 AMR exome AF: 0.468

Gnomad4 ASJ exome AF: 0.619

Gnomad4 EAS exome AF: 0.340

Gnomad4 SAS exome AF: 0.502

Gnomad4 FIN exome AF: 0.481

Gnomad4 NFE exome AF: 0.587

Gnomad4 OTH exome AF: 0.547

GnomAD4 genome AF: 0.511 AC: 77709 AN: 151952 Hom.: 20439 Cov.: 32 AF XY: 0.505 AC XY: 37475 AN XY: 74248

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.622

Gnomad4 EAS AF: 0.362

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.478

Gnomad4 NFE AF: 0.586

Gnomad4 OTH AF: 0.556

Alfa AF: 0.570 Hom.: 56569

Bravo AF: 0.509

TwinsUK AF: 0.584 AC: 2165

ALSPAC AF: 0.574 AC: 2213

ESP6500AA AF: 0.417 AC: 1838

ESP6500EA AF: 0.596 AC: 5129

ExAC AF: 0.523 AC: 63474

Asia WGS AF: 0.446 AC: 1550 AN: 3478

EpiCase AF: 0.588

EpiControl AF: 0.599

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.77
DEOGEN2	Benign	0.14	T;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.46	T;T;T;T;T
MetaRNN	Benign	0.0000030	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.090	N;.;.;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.39	N;N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.36	T;T;T;T;T
Sift4G	Benign	0.63	T;T;T;T;T
Polyphen		0.0	B;.;.;.;B
Vest4		0.042
MPC		0.19
ClinPred		0.0081	T
GERP RS		-2.6
Varity_R		0.025
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1545133; hg19: chr2-113309473; COSMIC: COSV54498765; COSMIC: COSV54498765;