rs2230944

Positions:

• chr12-124336867-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006312.6(NCOR2):​c.6001C>T​(p.Pro2001Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0457 in 1,611,108 control chromosomes in the GnomAD database, including 2,192 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.045 (172 hom., cov: 33)
  • Exomes 𝑓: 0.046 (2020 hom.)
• Consequence: NCOR2 NM_006312.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.437

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019736588).
• BP6: Variant 12-124336867-G-A is Benign according to our data. Variant chr12-124336867-G-A is described in ClinVar as [Benign]. Clinvar id is 3056105.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOR2	NM_006312.6	c.6001C>T	p.Pro2001Ser	missense_variant	40/49	ENST00000405201.6
NCOR2	NM_001206654.2	c.5971C>T	p.Pro1991Ser	missense_variant	39/48
NCOR2	NM_001077261.4	c.5971C>T	p.Pro1991Ser	missense_variant	39/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOR2	ENST00000405201.6	c.6001C>T	p.Pro2001Ser	missense_variant	40/49	1	NM_006312.6	P4
NCOR2	ENST00000429285.6	c.5971C>T	p.Pro1991Ser	missense_variant	38/47	1		A2
NCOR2	ENST00000404621.5	c.5971C>T	p.Pro1991Ser	missense_variant	38/47	1		A2

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6834 AN: 152154 Hom.: 173 Cov.: 33

Gnomad AFR AF: 0.0520

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0420

Gnomad OTH AF: 0.0401

GnomAD3 exomes AF: 0.0466 AC: 11316 AN: 242918 Hom.: 400 AF XY: 0.0510 AC XY: 6762 AN XY: 132530

Gnomad AFR exome AF: 0.0480

Gnomad AMR exome AF: 0.0252

Gnomad ASJ exome AF: 0.0334

Gnomad EAS exome AF: 0.0222

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.0419

Gnomad OTH exome AF: 0.0401

GnomAD4 exome AF: 0.0458 AC: 66758 AN: 1458836 Hom.: 2020 Cov.: 31 AF XY: 0.0481 AC XY: 34928 AN XY: 725704

Gnomad4 AFR exome AF: 0.0525

Gnomad4 AMR exome AF: 0.0273

Gnomad4 ASJ exome AF: 0.0316

Gnomad4 EAS exome AF: 0.0361

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.0221

Gnomad4 NFE exome AF: 0.0420

Gnomad4 OTH exome AF: 0.0462

GnomAD4 genome AF: 0.0449 AC: 6844 AN: 152272 Hom.: 172 Cov.: 33 AF XY: 0.0457 AC XY: 3402 AN XY: 74448

Gnomad4 AFR AF: 0.0521

Gnomad4 AMR AF: 0.0376

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.0284

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.0193

Gnomad4 NFE AF: 0.0420

Gnomad4 OTH AF: 0.0397

Alfa AF: 0.00784 Hom.: 47

Bravo AF: 0.0438

TwinsUK AF: 0.0372 AC: 138

ALSPAC AF: 0.0389 AC: 150

ESP6500AA AF: 0.0482 AC: 191

ESP6500EA AF: 0.0343 AC: 284

ExAC AF: 0.0486 AC: 5847

Asia WGS AF: 0.0850 AC: 297 AN: 3478

EpiCase AF: 0.0434

EpiControl AF: 0.0475

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NCOR2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 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	0.079
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.81
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.77	T;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.7	D;D;.;D;D
REVEL	Benign	0.068
Sift	Benign	0.081	T;T;.;D;T
Sift4G	Benign	0.17	T;T;T;T;T
Vest4		0.010
MPC		0.21
ClinPred		0.016	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.087
gMVP		0.24

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: rs2230944; hg19: chr12-124821413; COSMIC: COSV62297394; COSMIC: COSV62297394;