12-124325482-C-T

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.7465G>A(p.Ala2489Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,336,114 control chromosomes in the GnomAD database, including 728 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (91 hom., cov: 30)
  • Exomes 𝑓: 0.013 (637 hom.)
• Consequence: NCOR2 NM_006312.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.159

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=0.0015721619).
• BP6: Variant 12-124325482-C-T is Benign according to our data. Variant chr12-124325482-C-T is described in ClinVar as [Benign]. Clinvar id is 1271601.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOR2	NM_006312.6	c.7465G>A	p.Ala2489Thr	missense_variant	49/49	ENST00000405201.6
NCOR2	NM_001206654.2	c.7435G>A	p.Ala2479Thr	missense_variant	48/48
NCOR2	NM_001077261.4	c.7297G>A	p.Ala2433Thr	missense_variant	48/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOR2	ENST00000405201.6	c.7465G>A	p.Ala2489Thr	missense_variant	49/49	1	NM_006312.6	P4

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2611 AN: 146388 Hom.: 90 Cov.: 30

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00224

Gnomad AMR AF: 0.00566

Gnomad ASJ AF: 0.0108

Gnomad EAS AF: 0.0377

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0968

Gnomad MID AF: 0.0171

Gnomad NFE AF: 0.00530

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0536 AC: 1537 AN: 28692 Hom.: 92 AF XY: 0.0562 AC XY: 836 AN XY: 14866

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.00504

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.0375

Gnomad SAS exome AF: 0.176

Gnomad FIN exome AF: 0.0884

Gnomad NFE exome AF: 0.00561

Gnomad OTH exome AF: 0.0381

GnomAD4 exome AF: 0.0129 AC: 15364 AN: 1189626 Hom.: 637 Cov.: 38 AF XY: 0.0150 AC XY: 8666 AN XY: 578526

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.00358

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.0372

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.0817

Gnomad4 NFE exome AF: 0.00404

Gnomad4 OTH exome AF: 0.0208

GnomAD4 genome AF: 0.0179 AC: 2620 AN: 146488 Hom.: 91 Cov.: 30 AF XY: 0.0241 AC XY: 1709 AN XY: 71006

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.00565

Gnomad4 ASJ AF: 0.0108

Gnomad4 EAS AF: 0.0375

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0968

Gnomad4 NFE AF: 0.00530

Gnomad4 OTH AF: 0.0138

Alfa AF: 0.00917 Hom.: 14

Bravo AF: 0.00825

ESP6500AA AF: 0.00729 AC: 24

ESP6500EA AF: 0.00350 AC: 26

ExAC AF: 0.0135 AC: 1277

Asia WGS AF: 0.107 AC: 372 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	18
Dann	Benign	0.92
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.92	D;D;D;D;D
MetaRNN	Benign	0.0016	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.8	N;N;.;.;N
REVEL	Benign	0.049
Sift	Benign	0.14	T;T;.;.;T
Sift4G	Benign	0.30	T;T;T;T;T
Vest4		0.013
MPC		0.28
ClinPred		0.0098	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
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: rs77107801; hg19: chr12-124810028;