chr2-200921114-G-A

Variant names:

• chr2-200921114-G-A
• rs2307362
• NM_006190.5:c.1173C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_006190.5(ORC2):​c.1173C>T​(p.Leu391Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,592,800 control chromosomes in the GnomAD database, including 24,732 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4389 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20343 hom.)
• Consequence: ORC2 NM_006190.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• Publications: 21 publications found

Genes affected

ORC2 (HGNC:8488): (origin recognition complex subunit 2) The origin recognition complex (ORC) is a highly conserved six subunits protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. The protein encoded by this gene is a subunit of the ORC complex. This protein forms a core complex with ORC3, -4, and -5. It also interacts with CDC45 and MCM10, which are proteins known to be important for the initiation of DNA replication. This protein has been demonstrated to specifically associate with the origin of replication of Epstein-Barr virus in human cells, and is thought to be required for DNA replication from viral origin of replication. Alternatively spliced transcript variants have been found, one of which is a nonsense-mediated mRNA decay candidate. [provided by RefSeq, Oct 2010]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP7: Synonymous conserved (PhyloP=0.115 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORC2	NM_006190.5	c.1173C>T	p.Leu391Leu	synonymous_variant	Exon 14 of 18	ENST00000234296.7	NP_006181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC2	ENST00000234296.7	c.1173C>T	p.Leu391Leu	synonymous_variant	Exon 14 of 18	1	NM_006190.5	ENSP00000234296.2
ORC2	ENST00000464147.1	n.260C>T		non_coding_transcript_exon_variant	Exon 3 of 6	5
ORC2	ENST00000487853.1	n.625C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32783 AN: 151916 Hom.: 4381 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.00847

Gnomad SAS AF: 0.0690

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.209

GnomAD2 exomes AF: 0.154 AC: 37679 AN: 244142 AF XY: 0.150

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.207

Gnomad EAS exome AF: 0.00570

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.160 AC: 230199 AN: 1440766 Hom.: 20343 Cov.: 28 AF XY: 0.158 AC XY: 113000 AN XY: 717300

African (AFR) AF: 0.376 AC: 12291 AN: 32668

American (AMR) AF: 0.117 AC: 4990 AN: 42826

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 5349 AN: 25730

East Asian (EAS) AF: 0.00342 AC: 135 AN: 39472

South Asian (SAS) AF: 0.0770 AC: 6432 AN: 83582

European-Finnish (FIN) AF: 0.170 AC: 8972 AN: 52924

Middle Eastern (MID) AF: 0.161 AC: 920 AN: 5698

European-Non Finnish (NFE) AF: 0.165 AC: 181364 AN: 1098292

Other (OTH) AF: 0.164 AC: 9746 AN: 59574

GnomAD4 genome AF: 0.216 AC: 32832 AN: 152034 Hom.: 4389 Cov.: 32 AF XY: 0.211 AC XY: 15713 AN XY: 74324

African (AFR) AF: 0.372 AC: 15391 AN: 41416

American (AMR) AF: 0.163 AC: 2484 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 750 AN: 3470

East Asian (EAS) AF: 0.00849 AC: 44 AN: 5184

South Asian (SAS) AF: 0.0691 AC: 333 AN: 4820

European-Finnish (FIN) AF: 0.164 AC: 1731 AN: 10568

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11490 AN: 67998

Other (OTH) AF: 0.207 AC: 437 AN: 2108

Alfa AF: 0.167 Hom.: 1497

Bravo AF: 0.226

Asia WGS AF: 0.0700 AC: 243 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.6
DANN	Benign	0.68
PhyloP100		0.12
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2307362; hg19: chr2-201785837; COSMIC: COSV52238699;