Genetic Variant NM_006312.6:c.5312G>T (chr12-124340628-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006312.6(NCOR2):c.5312G>T(p.Arg1771Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,342,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R1771C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

NCOR2
NM_006312.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37772858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOR2	NM_006312.6 link	c.5312G>T	p.Arg1771Leu	missense_variant	Exon 37 of 49	ENST00000405201.6	NP_006303.4	Q9Y618-1
NCOR2	NM_001206654.2 link	c.5282G>T	p.Arg1761Leu	missense_variant	Exon 36 of 48		NP_001193583.1	Q9Y618C9J0Q5
NCOR2	NM_001077261.4 link	c.5282G>T	p.Arg1761Leu	missense_variant	Exon 36 of 48		NP_001070729.2	Q9Y618C9JE98

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOR2	ENST00000405201.6 link	c.5312G>T	p.Arg1771Leu	missense_variant	Exon 37 of 49	1	NM_006312.6	ENSP00000384018.1		Q9Y618-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000149

AC:

AN:

1342778

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

656812

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30044

American (AMR)

AF:

0.00

AC:

AN:

26914

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20302

East Asian (EAS)

AF:

0.00

AC:

AN:

37850

South Asian (SAS)

AF:

0.00

AC:

AN:

68592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5246

European-Non Finnish (NFE)

AF:

0.00000189

AC:

AN:

1059748

Other (OTH)

AF:

0.00

AC:

AN:

55620

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

0.0041

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Uncertain

-0.22

PhyloP100

3.4

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.9

D;D;.;.;D

REVEL

Benign

0.17

Sift

Uncertain

0.0010

D;D;.;.;D

Sift4G

Uncertain

0.011

D;D;D;D;D

Polyphen

1.0

.;.;.;.;D

Vest4

0.52

MutPred

0.27

Loss of solvent accessibility (P = 0.0022);.;.;.;.;

MVP

0.64

MPC

0.79

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.47

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over