Genetic Variant NM_006312.6:c.7433C>T (chr12-124325514-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_006312.6(NCOR2):c.7433C>T(p.Pro2478Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000957 in 1,358,714 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2478S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

NCOR2
NM_006312.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.25

Publications

0 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37633726).

BS2

High AC in GnomAdExome4 at 12 AD gene.

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.7433C>T	p.Pro2478Leu	missense	Exon 49 of 49	NP_006303.4	Q9Y618-1
NCOR2	NM_001206654.2		c.7403C>T	p.Pro2468Leu	missense	Exon 48 of 48	NP_001193583.1	C9J0Q5
NCOR2	NM_001077261.4		c.7265C>T	p.Pro2422Leu	missense	Exon 48 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.7433C>T	p.Pro2478Leu	missense	Exon 49 of 49	ENSP00000384018.1	Q9Y618-1
NCOR2	ENST00000429285.6	TSL:1	c.7403C>T	p.Pro2468Leu	missense	Exon 47 of 47	ENSP00000400281.2	C9J0Q5
NCOR2	ENST00000404621.5	TSL:1	c.7265C>T	p.Pro2422Leu	missense	Exon 47 of 47	ENSP00000384202.1	C9JE98

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000314

AC:

AN:

31860

AF XY:

0.0000615

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000995

AC:

AN:

1206606

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

585646

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24690

American (AMR)

AF:

0.00

AC:

AN:

11002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16388

East Asian (EAS)

AF:

0.00

AC:

AN:

28942

South Asian (SAS)

AF:

0.00

AC:

AN:

48070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4066

European-Non Finnish (NFE)

AF:

0.0000122

AC:

AN:

983696

Other (OTH)

AF:

0.00

AC:

AN:

48494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

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:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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.:

ExAC

AF:

0.00000986

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.14

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.38

MetaSVM

Benign

-1.1

PhyloP100

5.2

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.13

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Vest4

0.28

MVP

0.35

MPC

0.58

ClinPred

0.78

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.2

Varity_R

0.25

gMVP

0.25

Mutation Taster

=91/9

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