2-112551896-C-T

Variant names:

• chr2-112551896-C-T
• rs1545133
• NM_019014.6:c.884C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 35 publications found

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 Gene-Disease associations (from GenCC):

• Treacher Collins syndrome 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• Treacher-Collins syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019014.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1B	NM_019014.6	MANE Select	c.884C>T	p.Ser295Leu	missense	Exon 6 of 15	NP_061887.2
	POLR1B	NM_001371969.1		c.884C>T	p.Ser295Leu	missense	Exon 6 of 16	NP_001358898.1
	POLR1B	NM_001282772.2		c.998C>T	p.Ser333Leu	missense	Exon 7 of 16	NP_001269701.1	Q9H9Y6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1B	ENST00000263331.10	TSL:2 MANE Select	c.884C>T	p.Ser295Leu	missense	Exon 6 of 15	ENSP00000263331.5	Q9H9Y6-1
	POLR1B	ENST00000409894.7	TSL:1	c.884C>T	p.Ser295Leu	missense	Exon 6 of 13	ENSP00000387143.3	Q9H9Y6-5
	POLR1B	ENST00000333990.10	TSL:1	n.*754C>T		non_coding_transcript_exon	Exon 7 of 16	ENSP00000334589.6	F8WAK7

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

GnomAD2 exomes AF: 0.522 AC: 131281 AN: 251460 AF XY: 0.528

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 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

African (AFR) AF: 0.412 AC: 13781 AN: 33468

American (AMR) AF: 0.468 AC: 20925 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 16165 AN: 26128

East Asian (EAS) AF: 0.340 AC: 13498 AN: 39698

South Asian (SAS) AF: 0.502 AC: 43333 AN: 86246

European-Finnish (FIN) AF: 0.481 AC: 25691 AN: 53418

Middle Eastern (MID) AF: 0.631 AC: 3638 AN: 5766

European-Non Finnish (NFE) AF: 0.587 AC: 652763 AN: 1111600

Other (OTH) AF: 0.547 AC: 32999 AN: 60376

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

African (AFR) AF: 0.412 AC: 17062 AN: 41408

American (AMR) AF: 0.497 AC: 7588 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2157 AN: 3470

East Asian (EAS) AF: 0.362 AC: 1870 AN: 5164

South Asian (SAS) AF: 0.495 AC: 2381 AN: 4814

European-Finnish (FIN) AF: 0.478 AC: 5040 AN: 10548

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39810 AN: 67962

Other (OTH) AF: 0.556 AC: 1172 AN: 2108

Alfa AF: 0.559 Hom.: 110420

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0000030	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.090	N
PhyloP100		-0.084
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.016
Sift	Benign	0.36	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.19
ClinPred		0.0081	T
GERP RS		-2.6
Varity_R		0.025
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1545133; hg19: chr2-113309473; COSMIC: COSV54498765; COSMIC: COSV54498765;