chr12-124372487-C-A

Variant names:

• chr12-124372487-C-A
• rs7978237
• NM_006312.6:c.2342G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006312.6(NCOR2):​c.2342G>T​(p.Gly781Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,425,288 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: not found (cov: 27)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NCOR2 NM_006312.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.679
• 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: 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=0.057995766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOR2	NM_006312.6	c.2342G>T	p.Gly781Val	missense_variant	Exon 22 of 49	ENST00000405201.6	NP_006303.4
NCOR2	NM_001206654.2	c.2288G>T	p.Gly763Val	missense_variant	Exon 21 of 48		NP_001193583.1
NCOR2	NM_001077261.4	c.2288G>T	p.Gly763Val	missense_variant	Exon 21 of 48		NP_001070729.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOR2	ENST00000405201.6	c.2342G>T	p.Gly781Val	missense_variant	Exon 22 of 49	1	NM_006312.6	ENSP00000384018.1

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149986 Hom.: 0 Cov.: 27

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: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1425288 Hom.: 0 Cov.: 39 AF XY: 0.00000282 AC XY: 2 AN XY: 708572

African (AFR) AF: 0.00 AC: 0 AN: 32594

American (AMR) AF: 0.00 AC: 0 AN: 41322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24522

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.00 AC: 0 AN: 83516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5170

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1102238

Other (OTH) AF: 0.00 AC: 0 AN: 59246

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.56
DEOGEN2	Benign	0.28	T;.;.;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.54	T;T;T;T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.058	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;.;.;.;.
PhyloP100		0.68
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.030	N;N;.;.;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.14	T;T;.;.;T;T;D
Sift4G	Uncertain	0.023	D;D;D;D;D;.;.
Polyphen		0.0	.;.;.;.;B;.;.
Vest4		0.15
MutPred		0.26		Loss of glycosylation at P780 (P = 0.0933);.;.;.;.;Loss of glycosylation at P780 (P = 0.0933);.;
MVP		0.31
MPC		0.21
ClinPred		0.052	T
GERP RS		-0.62
Varity_R		0.053
gMVP		0.27
Mutation Taster		=99/1	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: rs7978237; hg19: chr12-124857033;