2-200949574-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006190.5(ORC2):c.308C>A(p.Ser103Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,580,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

ORC2
NM_006190.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.75

Variant links:

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]

ORC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18785197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC2	NM_006190.5 linkuse as main transcript	c.308C>A	p.Ser103Tyr	missense_variant	5/18	ENST00000234296.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ORC2	ENST00000234296.7 linkuse as main transcript	c.308C>A	p.Ser103Tyr	missense_variant	5/18	1	NM_006190.5	P1
ORC2	ENST00000410039.5 linkuse as main transcript	c.308C>A	p.Ser103Tyr	missense_variant	5/5	5
ORC2	ENST00000467605.5 linkuse as main transcript	n.454C>A		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000446

AC:

AN:

246696

Hom.:

AF XY:

0.0000525

AC XY:

AN XY:

133312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000891

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000176

AC:

251

AN:

1428848

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

118

AN XY:

712584

show subpopulations

Gnomad4 AFR exome

AF:

0.000122

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:

0.000221

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000551

EpiControl

AF:

0.000180

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The c.308C>A (p.S103Y) alteration is located in exon 5 (coding exon 3) of the ORC2 gene. This alteration results from a C to A substitution at nucleotide position 308, causing the serine (S) at amino acid position 103 to be replaced by a tyrosine (Y). 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

Benign

0.14

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.43

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Benign

0.097

T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

0.88

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.049

Sift

Benign

0.051

T;D

Sift4G

Uncertain

0.043

D;.

Polyphen

0.86

P;.

Vest4

0.16

MVP

0.39

MPC

0.32

ClinPred

0.15

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over