12-124341916-C-T

Variant names:

• chr12-124341916-C-T
• rs2229840
• NM_006312.6:c.5095G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006312.6(NCOR2):​c.5095G>A​(p.Ala1699Thr) variant causes a missense change. The variant allele was found at a frequency of 0.16 in 1,612,822 control chromosomes in the GnomAD database, including 21,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1787 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19665 hom.)
• Consequence: NCOR2 NM_006312.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.72
• Publications: 51 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014859438).
• BP6: Variant 12-124341916-C-T is Benign according to our data. Variant chr12-124341916-C-T is described in ClinVar as Benign. ClinVar VariationId is 1278544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOR2	NM_006312.6	c.5095G>A	p.Ala1699Thr	missense_variant	Exon 36 of 49	ENST00000405201.6	NP_006303.4
NCOR2	NM_001206654.2	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 35 of 48		NP_001193583.1
NCOR2	NM_001077261.4	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 35 of 48		NP_001070729.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOR2	ENST00000405201.6	c.5095G>A	p.Ala1699Thr	missense_variant	Exon 36 of 49	1	NM_006312.6	ENSP00000384018.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22784 AN: 152122 Hom.: 1787 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.171 AC: 42357 AN: 247884 AF XY: 0.171

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.161 AC: 235609 AN: 1460582 Hom.: 19665 Cov.: 34 AF XY: 0.162 AC XY: 117615 AN XY: 726590

African (AFR) AF: 0.114 AC: 3801 AN: 33476

American (AMR) AF: 0.242 AC: 10802 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4253 AN: 26132

East Asian (EAS) AF: 0.120 AC: 4759 AN: 39698

South Asian (SAS) AF: 0.197 AC: 16969 AN: 86258

European-Finnish (FIN) AF: 0.144 AC: 7498 AN: 52234

Middle Eastern (MID) AF: 0.165 AC: 949 AN: 5768

European-Non Finnish (NFE) AF: 0.159 AC: 177316 AN: 1111920

Other (OTH) AF: 0.153 AC: 9262 AN: 60376

GnomAD4 genome AF: 0.150 AC: 22785 AN: 152240 Hom.: 1787 Cov.: 33 AF XY: 0.149 AC XY: 11101 AN XY: 74426

African (AFR) AF: 0.117 AC: 4877 AN: 41542

American (AMR) AF: 0.199 AC: 3046 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3472

East Asian (EAS) AF: 0.112 AC: 578 AN: 5182

South Asian (SAS) AF: 0.190 AC: 916 AN: 4826

European-Finnish (FIN) AF: 0.142 AC: 1509 AN: 10598

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10705 AN: 68010

Other (OTH) AF: 0.167 AC: 353 AN: 2114

Alfa AF: 0.157 Hom.: 7641

Bravo AF: 0.153

TwinsUK AF: 0.158 AC: 585

ALSPAC AF: 0.163 AC: 630

ESP6500AA AF: 0.116 AC: 505

ESP6500EA AF: 0.162 AC: 1392

ExAC AF: 0.169 AC: 20484

Asia WGS AF: 0.135 AC: 467 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.158

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 20, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

NCOR2-related disorder Benign:1

Oct 30, 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	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Benign	0.097
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
MetaRNN	Benign	0.0015	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		4.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	N;N;.;.;N
REVEL	Benign	0.094
Sift	Benign	0.21	T;T;.;.;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.92	.;.;.;.;P
Vest4		0.14
MPC		0.69
ClinPred		0.060	T
GERP RS		4.4
PromoterAI		0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.67
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: rs2229840; hg19: chr12-124826462; COSMIC: COSV62295615; COSMIC: COSV62295615;