2-200940249-G-T

Variant names:

• chr2-200940249-G-T
• rs13408964
• NM_006190.5:c.453+999C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006190.5(ORC2):​c.453+999C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,096 control chromosomes in the GnomAD database, including 4,391 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 (4391 hom., cov: 32)
• Consequence: ORC2 NM_006190.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006190.5. 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
	ORC2	NM_006190.5	MANE Select	c.453+999C>A		intron	N/A	NP_006181.1
	ORC2	NR_033915.2		n.683+999C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC2	ENST00000234296.7	TSL:1 MANE Select	c.453+999C>A		intron	N/A	ENSP00000234296.2
	ORC2	ENST00000474877.1	TSL:4	n.197+999C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32784 AN: 151978 Hom.: 4383 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.00846

Gnomad SAS AF: 0.0692

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.209

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.216 AC: 32833 AN: 152096 Hom.: 4391 Cov.: 32 AF XY: 0.211 AC XY: 15724 AN XY: 74364

African (AFR) AF: 0.373 AC: 15452 AN: 41470

American (AMR) AF: 0.162 AC: 2478 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 749 AN: 3470

East Asian (EAS) AF: 0.00848 AC: 44 AN: 5186

South Asian (SAS) AF: 0.0693 AC: 334 AN: 4820

European-Finnish (FIN) AF: 0.164 AC: 1736 AN: 10570

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11432 AN: 67984

Other (OTH) AF: 0.207 AC: 437 AN: 2110

Alfa AF: 0.201 Hom.: 468

Bravo AF: 0.225

Asia WGS AF: 0.0700 AC: 243 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.92
PhyloP100		0.36
Mutation Taster		=100/0	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: rs13408964; hg19: chr2-201804972;