chr12-124372487-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_006312.6(NCOR2):​c.2342G>A​(p.Gly781Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,574,702 control chromosomes in the GnomAD database, including 15,190 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1230 hom., cov: 27)
  • Exomes 𝑓: 0.14 (13960 hom.)
• Consequence: NCOR2 NM_006312.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.679
• Publications: 16 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014986098).
• BP6: Variant 12-124372487-C-T is Benign according to our data. Variant chr12-124372487-C-T is described in ClinVar as Benign. ClinVar VariationId is 3058956.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOR2	NM_006312.6	c.2342G>A	p.Gly781Glu	missense_variant	Exon 22 of 49	ENST00000405201.6	NP_006303.4
NCOR2	NM_001206654.2	c.2288G>A	p.Gly763Glu	missense_variant	Exon 21 of 48		NP_001193583.1
NCOR2	NM_001077261.4	c.2288G>A	p.Gly763Glu	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>A	p.Gly781Glu	missense_variant	Exon 22 of 49	1	NM_006312.6	ENSP00000384018.1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17371 AN: 149774 Hom.: 1226 Cov.: 27

Gnomad AFR AF: 0.0836

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.0702

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.118 AC: 24785 AN: 210060 AF XY: 0.117

Gnomad AFR exome AF: 0.0869

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.135 AC: 192640 AN: 1424812 Hom.: 13960 Cov.: 39 AF XY: 0.134 AC XY: 94879 AN XY: 708336

African (AFR) AF: 0.0802 AC: 2613 AN: 32582

American (AMR) AF: 0.135 AC: 5562 AN: 41306

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3499 AN: 24518

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39500

South Asian (SAS) AF: 0.0875 AC: 7309 AN: 83498

European-Finnish (FIN) AF: 0.161 AC: 5969 AN: 37172

Middle Eastern (MID) AF: 0.0938 AC: 485 AN: 5168

European-Non Finnish (NFE) AF: 0.145 AC: 159439 AN: 1101838

Other (OTH) AF: 0.131 AC: 7758 AN: 59230

GnomAD4 genome AF: 0.116 AC: 17385 AN: 149890 Hom.: 1230 Cov.: 27 AF XY: 0.114 AC XY: 8314 AN XY: 73142

African (AFR) AF: 0.0837 AC: 3413 AN: 40776

American (AMR) AF: 0.129 AC: 1940 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 456 AN: 3446

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5148

South Asian (SAS) AF: 0.0700 AC: 330 AN: 4712

European-Finnish (FIN) AF: 0.130 AC: 1341 AN: 10308

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9493 AN: 67196

Other (OTH) AF: 0.118 AC: 245 AN: 2076

Alfa AF: 0.0951 Hom.: 216

Bravo AF: 0.116

TwinsUK AF: 0.147 AC: 545

ALSPAC AF: 0.148 AC: 569

ESP6500AA AF: 0.0734 AC: 277

ESP6500EA AF: 0.140 AC: 1147

ExAC AF: 0.120 AC: 14201

Asia WGS AF: 0.0330 AC: 114 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NCOR2-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.2
DANN	Benign	0.45
DEOGEN2	Benign	0.26	T;.;.;.;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.26	T;T;T;T;T;T;T
MetaRNN	Benign	0.0015	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;.;.;.;.;.;.
PhyloP100		0.68
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.4	N;N;.;.;N;N;N
REVEL	Benign	0.032
Sift	Benign	0.93	T;T;.;.;T;T;D
Sift4G	Benign	0.16	T;T;T;T;T;.;.
Polyphen		0.0	.;.;.;.;B;.;.
Vest4		0.029
MPC		0.22
ClinPred		0.0016	T
GERP RS		-0.62
Varity_R		0.042
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV62296476;