12-124336867-G-C

Variant names:

• chr12-124336867-G-C
• rs2230944
• NM_006312.6:c.6001C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006312.6(NCOR2):​c.6001C>G​(p.Pro2001Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. P2001S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NCOR2 NM_006312.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.437
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12615731).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOR2	NM_006312.6	MANE Select	c.6001C>G	p.Pro2001Ala	missense	Exon 40 of 49	NP_006303.4
	NCOR2	NM_001206654.2		c.5971C>G	p.Pro1991Ala	missense	Exon 39 of 48	NP_001193583.1
	NCOR2	NM_001077261.4		c.5971C>G	p.Pro1991Ala	missense	Exon 39 of 48	NP_001070729.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOR2	ENST00000405201.6	TSL:1 MANE Select	c.6001C>G	p.Pro2001Ala	missense	Exon 40 of 49	ENSP00000384018.1
	NCOR2	ENST00000429285.6	TSL:1	c.5971C>G	p.Pro1991Ala	missense	Exon 38 of 47	ENSP00000400281.2
	NCOR2	ENST00000404621.5	TSL:1	c.5971C>G	p.Pro1991Ala	missense	Exon 38 of 47	ENSP00000384202.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725724

African (AFR) AF: 0.00 AC: 0 AN: 33344

American (AMR) AF: 0.00 AC: 0 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110864

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.81
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.44
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.078
Sift	Benign	0.030	D
Sift4G	Benign	0.61	T
Vest4		0.067
MVP		0.32
MPC		0.18
ClinPred		0.092	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.069
gMVP		0.21
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs2230944; hg19: chr12-124821413;