2-112574844-T-C

Variant names:

• chr2-112574844-T-C
• rs10169344
• NM_019014.6:c.2526-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000263331.10(POLR1B):​c.2526-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,601,208 control chromosomes in the GnomAD database, including 11,404 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2114 hom., cov: 32)
  • Exomes 𝑓: 0.099 (9290 hom.)
• Consequence: POLR1B ENST00000263331.10 splice_region, intron
• Scores: Splicing: ADA: 0.00006692
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0740
• Publications: 10 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, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), 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 (BayesDel_noAF=-0.75).
• BP6: Variant 2-112574844-T-C is Benign according to our data. Variant chr2-112574844-T-C is described in ClinVar as Benign. ClinVar VariationId is 1177727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000263331.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1B	NM_019014.6	MANE Select	c.2526-3T>C		splice_region intron	N/A	NP_061887.2
	POLR1B	NM_001371969.1		c.2664-3T>C		splice_region intron	N/A	NP_001358898.1
	POLR1B	NM_001282772.2		c.2640-3T>C		splice_region intron	N/A	NP_001269701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1B	ENST00000263331.10	TSL:2 MANE Select	c.2526-3T>C		splice_region intron	N/A	ENSP00000263331.5
	POLR1B	ENST00000409894.7	TSL:1	c.1977-3T>C		splice_region intron	N/A	ENSP00000387143.3
	POLR1B	ENST00000333990.10	TSL:1	n.*2396-3T>C		splice_region intron	N/A	ENSP00000334589.6

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21743 AN: 151970 Hom.: 2105 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.0523

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.132 AC: 32623 AN: 246606 AF XY: 0.125

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.0717

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0753

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0993 AC: 143915 AN: 1449120 Hom.: 9290 Cov.: 32 AF XY: 0.0990 AC XY: 71142 AN XY: 718832

African (AFR) AF: 0.249 AC: 8265 AN: 33178

American (AMR) AF: 0.221 AC: 9736 AN: 44030

Ashkenazi Jewish (ASJ) AF: 0.0724 AC: 1862 AN: 25724

East Asian (EAS) AF: 0.314 AC: 12368 AN: 39410

South Asian (SAS) AF: 0.136 AC: 11605 AN: 85348

European-Finnish (FIN) AF: 0.0512 AC: 2722 AN: 53198

Middle Eastern (MID) AF: 0.0814 AC: 465 AN: 5714

European-Non Finnish (NFE) AF: 0.0816 AC: 89954 AN: 1102640

Other (OTH) AF: 0.116 AC: 6938 AN: 59878

GnomAD4 genome AF: 0.143 AC: 21784 AN: 152088 Hom.: 2114 Cov.: 32 AF XY: 0.143 AC XY: 10657 AN XY: 74360

African (AFR) AF: 0.250 AC: 10370 AN: 41444

American (AMR) AF: 0.177 AC: 2698 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 243 AN: 3470

East Asian (EAS) AF: 0.308 AC: 1592 AN: 5170

South Asian (SAS) AF: 0.146 AC: 703 AN: 4816

European-Finnish (FIN) AF: 0.0523 AC: 554 AN: 10584

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0754 AC: 5131 AN: 68008

Other (OTH) AF: 0.127 AC: 269 AN: 2112

Alfa AF: 0.102 Hom.: 784

Bravo AF: 0.161

Asia WGS AF: 0.234 AC: 815 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Benign	0.77
PhyloP100		-0.074
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 6

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

Other links and lift over

dbSNP: rs10169344; hg19: chr2-113332421; COSMIC: COSV54496062; COSMIC: COSV54496062;