chr12-124325500-C-A

Variant names:

• chr12-124325500-C-A
• rs745312035
• NM_006312.6:c.7447G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006312.6(NCOR2):​c.7447G>T​(p.Ala2483Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000812 in 1,355,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A2483V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: NCOR2 NM_006312.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.336
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04762718).
• BS2: High AC in GnomAdExome4 at 10 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOR2	NM_006312.6	MANE Select	c.7447G>T	p.Ala2483Ser	missense	Exon 49 of 49	NP_006303.4	Q9Y618-1
	NCOR2	NM_001206654.2		c.7417G>T	p.Ala2473Ser	missense	Exon 48 of 48	NP_001193583.1	C9J0Q5
	NCOR2	NM_001077261.4		c.7279G>T	p.Ala2427Ser	missense	Exon 48 of 48	NP_001070729.2	C9JE98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOR2	ENST00000405201.6	TSL:1 MANE Select	c.7447G>T	p.Ala2483Ser	missense	Exon 49 of 49	ENSP00000384018.1	Q9Y618-1
	NCOR2	ENST00000429285.6	TSL:1	c.7417G>T	p.Ala2473Ser	missense	Exon 47 of 47	ENSP00000400281.2	C9J0Q5
	NCOR2	ENST00000404621.5	TSL:1	c.7279G>T	p.Ala2427Ser	missense	Exon 47 of 47	ENSP00000384202.1	C9JE98

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151950 Hom.: 0 Cov.: 30

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: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000379 AC: 1 AN: 26416 AF XY: 0.0000746

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: 0.000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000831 AC: 10 AN: 1203186 Hom.: 0 Cov.: 37 AF XY: 0.00000856 AC XY: 5 AN XY: 584236

African (AFR) AF: 0.00 AC: 0 AN: 24420

American (AMR) AF: 0.00 AC: 0 AN: 11094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16412

East Asian (EAS) AF: 0.00 AC: 0 AN: 28406

South Asian (SAS) AF: 0.00 AC: 0 AN: 47418

European-Finnish (FIN) AF: 0.000146 AC: 6 AN: 41102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3758

European-Non Finnish (NFE) AF: 0.00000204 AC: 2 AN: 982246

Other (OTH) AF: 0.0000414 AC: 2 AN: 48330

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151950 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000103 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.84
DANN	Benign	0.71
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.34
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.019
Sift	Benign	0.18	T
Sift4G	Benign	0.67	T
Vest4		0.058
MVP		0.27
MPC		0.19
ClinPred		0.017	T
GERP RS		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.11
Mutation Taster		=96/4	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: rs745312035; hg19: chr12-124810046;