Genetic Variant NCOR2:p.Ser2453Ser (chr12-124326195-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_006312.6(NCOR2):c.7359C>T(p.Ser2453Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,524,860 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00046 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

NCOR2
NM_006312.6 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -4.37

Variant links:

Genes affected

NCOR2 (HGNC:7673): (nuclear receptor corepressor 2) This gene encodes a nuclear receptor co-repressor that mediates transcriptional silencing of certain target genes. The encoded protein is a member of a family of thyroid hormone- and retinoic acid receptor-associated co-repressors. This protein acts as part of a multisubunit complex which includes histone deacetylases to modify chromatin structure that prevents basal transcriptional activity of target genes. Aberrant expression of this gene is associated with certain cancers. Alternate splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Apr 2011]

NCOR2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.113).

BP6

Variant 12-124326195-G-A is Benign according to our data. Variant chr12-124326195-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3047964.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-4.37 with no splicing effect.

BS2

High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOR2	NM_006312.6 link	c.7359C>T	p.Ser2453Ser	synonymous_variant	Exon 48 of 49	ENST00000405201.6	NP_006303.4	Q9Y618-1
NCOR2	NM_001206654.2 link	c.7329C>T	p.Ser2443Ser	synonymous_variant	Exon 47 of 48		NP_001193583.1	Q9Y618C9J0Q5
NCOR2	NM_001077261.4 link	c.7191C>T	p.Ser2397Ser	synonymous_variant	Exon 47 of 48		NP_001070729.2	Q9Y618C9JE98

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOR2	ENST00000405201.6 link	c.7359C>T	p.Ser2453Ser	synonymous_variant	Exon 48 of 49	1	NM_006312.6	ENSP00000384018.1		Q9Y618-1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00983

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000678

AC:

AN:

126888

AF XY:

0.000644

show subpopulations

Gnomad AFR exome

AF:

0.000626

Gnomad AMR exome

AF:

0.0000888

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00877

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000836

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000274

AC:

376

AN:

1372532

Hom.:

Cov.:

AF XY:

0.000284

AC XY:

192

AN XY:

677086

show subpopulations

African (AFR)

AF:

0.000297

AC:

AN:

30306

American (AMR)

AF:

0.0000894

AC:

AN:

33570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24194

East Asian (EAS)

AF:

0.00564

AC:

192

AN:

34064

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77360

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40788

Middle Eastern (MID)

AF:

0.000394

AC:

AN:

5082

European-Non Finnish (NFE)

AF:

0.000130

AC:

139

AN:

1070102

Other (OTH)

AF:

0.000526

AC:

AN:

57066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000460

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41574

American (AMR)

AF:

0.0000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00986

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000192

Hom.:

Bravo

AF:

0.000582

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NCOR2-related disorder

Benign:1

Feb 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.1

(source)

DANN

Benign

0.71

PhyloP100

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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12-124326195-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over