chr12-124372487-C-T

Position:

• chr12-124372487-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000405201.6(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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1230 hom., cov: 27)
  • Exomes 𝑓: 0.14 (13960 hom.)
• Consequence: NCOR2 ENST00000405201.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.679

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

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
NCOR2	NM_006312.6	c.2342G>A	p.Gly781Glu	missense_variant	22/49	ENST00000405201.6	NP_006303.4
NCOR2	NM_001206654.2	c.2288G>A	p.Gly763Glu	missense_variant	21/48		NP_001193583.1
NCOR2	NM_001077261.4	c.2288G>A	p.Gly763Glu	missense_variant	21/48		NP_001070729.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCOR2	ENST00000405201.6	c.2342G>A	p.Gly781Glu	missense_variant	22/49	1	NM_006312.6	ENSP00000384018	P4

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

GnomAD3 exomes AF: 0.118 AC: 24785 AN: 210060 Hom.: 1702 AF XY: 0.117 AC XY: 13600 AN XY: 115994

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 SAS exome AF: 0.0835

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

Gnomad4 AFR exome AF: 0.0802

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0875

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.131

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

Gnomad4 AFR AF: 0.0837

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.0700

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.118

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs7978237; hg19: chr12-124857033; COSMIC: COSV62296476;