2-200913299-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006190.5(ORC2):c.1643A>C(p.Lys548Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,440,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ORC2 NM_006190.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC2	NM_006190.5	c.1643A>C	p.Lys548Thr	missense_variant	17/18	ENST00000234296.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC2	ENST00000234296.7	c.1643A>C	p.Lys548Thr	missense_variant	17/18	1	NM_006190.5	P1
ORC2	ENST00000464147.1	n.1247A>C		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440096 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 716948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.11e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2023

The c.1643A>C (p.K548T) alteration is located in exon 17 (coding exon 15) of the ORC2 gene. This alteration results from a A to C substitution at nucleotide position 1643, causing the lysine (K) at amino acid position 548 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.79		Loss of catalytic residue at K548 (P = 0.0215);
MVP		0.43
MPC		0.74
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.76
gMVP		0.59

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-201778022;