Genetic Variant NM_006312.6:c.2342G>C (chr12-124372487-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006312.6(NCOR2):c.2342G>C(p.Gly781Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000317 in 1,575,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G781E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NCOR2
NM_006312.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.679

Publications

16 publications found

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027313858).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006312.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCOR2	NM_006312.6	MANE Select	c.2342G>C	p.Gly781Ala	missense	Exon 22 of 49	NP_006303.4	Q9Y618-1
NCOR2	NM_001206654.2		c.2288G>C	p.Gly763Ala	missense	Exon 21 of 48	NP_001193583.1	C9J0Q5
NCOR2	NM_001077261.4		c.2288G>C	p.Gly763Ala	missense	Exon 21 of 48	NP_001070729.2	C9JE98

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCOR2	ENST00000405201.6	TSL:1 MANE Select	c.2342G>C	p.Gly781Ala	missense	Exon 22 of 49	ENSP00000384018.1	Q9Y618-1
NCOR2	ENST00000429285.6	TSL:1	c.2288G>C	p.Gly763Ala	missense	Exon 20 of 47	ENSP00000400281.2	C9J0Q5
NCOR2	ENST00000404621.5	TSL:1	c.2288G>C	p.Gly763Ala	missense	Exon 20 of 47	ENSP00000384202.1	C9JE98

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

149986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000737

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000476

AC:

AN:

210060

AF XY:

0.00000862

show subpopulations

Gnomad AFR exome

AF:

0.0000712

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1425288

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708572

show subpopulations

African (AFR)

AF:

0.0000614

AC:

AN:

32594

American (AMR)

AF:

0.00

AC:

AN:

41322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24522

East Asian (EAS)

AF:

0.00

AC:

AN:

39500

South Asian (SAS)

AF:

0.00

AC:

AN:

83516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5170

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102238

Other (OTH)

AF:

0.00

AC:

AN:

59246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000200

AC:

AN:

149986

Hom.:

Cov.:

AF XY:

0.0000410

AC XY:

AN XY:

73112

show subpopulations

African (AFR)

AF:

0.0000737

AC:

AN:

40694

American (AMR)

AF:

0.00

AC:

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67320

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

216

ExAC

AF:

0.00000842

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.58

CADD

Benign

6.7

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.23

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.37

M_CAP

Benign

0.031

MetaRNN

Benign

0.027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PhyloP100

0.68

PrimateAI

Benign

0.42

PROVEAN

Benign

0.45

REVEL

Benign

0.020

Sift

Benign

1.0

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.069

MutPred

0.24

Loss of catalytic residue at G781 (P = 0.0932)

MVP

0.29

MPC

0.18

ClinPred

0.031

GERP RS

-0.62

Varity_R

0.044

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over