chr12-124325482-C-T

Variant names:

• chr12-124325482-C-T
• rs77107801
• NM_006312.6:c.7465G>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.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. 13/20 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.159
• Publications: 1 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=0.0015721619).
• BP6: Variant 12-124325482-C-T is Benign according to our data. Variant chr12-124325482-C-T is described in ClinVar as Benign. ClinVar VariationId is 1271601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006312.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOR2	NM_006312.6	MANE Select	c.7465G>A	p.Ala2489Thr	missense	Exon 49 of 49	NP_006303.4	Q9Y618-1
	NCOR2	NM_001206654.2		c.7435G>A	p.Ala2479Thr	missense	Exon 48 of 48	NP_001193583.1	C9J0Q5
	NCOR2	NM_001077261.4		c.7297G>A	p.Ala2433Thr	missense	Exon 48 of 48	NP_001070729.2	C9JE98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOR2	ENST00000405201.6	TSL:1 MANE Select	c.7465G>A	p.Ala2489Thr	missense	Exon 49 of 49	ENSP00000384018.1	Q9Y618-1
	NCOR2	ENST00000429285.6	TSL:1	c.7435G>A	p.Ala2479Thr	missense	Exon 47 of 47	ENSP00000400281.2	C9J0Q5
	NCOR2	ENST00000404621.5	TSL:1	c.7297G>A	p.Ala2433Thr	missense	Exon 47 of 47	ENSP00000384202.1	C9JE98

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

GnomAD2 exomes AF: 0.0536 AC: 1537 AN: 28692 AF XY: 0.0562

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 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

African (AFR) AF: 0.0130 AC: 311 AN: 23912

American (AMR) AF: 0.00358 AC: 40 AN: 11162

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 160 AN: 15942

East Asian (EAS) AF: 0.0372 AC: 1021 AN: 27444

South Asian (SAS) AF: 0.117 AC: 5587 AN: 47810

European-Finnish (FIN) AF: 0.0817 AC: 3284 AN: 40202

Middle Eastern (MID) AF: 0.0134 AC: 47 AN: 3512

European-Non Finnish (NFE) AF: 0.00404 AC: 3931 AN: 972458

Other (OTH) AF: 0.0208 AC: 983 AN: 47184

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

African (AFR) AF: 0.0118 AC: 473 AN: 40150

American (AMR) AF: 0.00565 AC: 79 AN: 13978

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 37 AN: 3424

East Asian (EAS) AF: 0.0375 AC: 185 AN: 4928

South Asian (SAS) AF: 0.119 AC: 548 AN: 4606

European-Finnish (FIN) AF: 0.0968 AC: 910 AN: 9400

Middle Eastern (MID) AF: 0.0147 AC: 4 AN: 272

European-Non Finnish (NFE) AF: 0.00530 AC: 354 AN: 66804

Other (OTH) AF: 0.0138 AC: 28 AN: 2034

Alfa AF: 0.00931 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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.16
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.049
Sift	Benign	0.14	T
Sift4G	Benign	0.30	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
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: rs77107801; hg19: chr12-124810028;