rs2034543440

Variant names:

• chr12-124325446-G-A
• rs2034543440
• NM_006312.6:c.7501C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006312.6(NCOR2):​c.7501C>T​(p.Pro2501Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 145,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NCOR2 NM_006312.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.68
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.7501C>T	p.Pro2501Ser	missense	Exon 49 of 49	NP_006303.4	Q9Y618-1
	NCOR2	NM_001206654.2		c.7471C>T	p.Pro2491Ser	missense	Exon 48 of 48	NP_001193583.1	C9J0Q5
	NCOR2	NM_001077261.4		c.7333C>T	p.Pro2445Ser	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.7501C>T	p.Pro2501Ser	missense	Exon 49 of 49	ENSP00000384018.1	Q9Y618-1
	NCOR2	ENST00000429285.6	TSL:1	c.7471C>T	p.Pro2491Ser	missense	Exon 47 of 47	ENSP00000400281.2	C9J0Q5
	NCOR2	ENST00000404621.5	TSL:1	c.7333C>T	p.Pro2445Ser	missense	Exon 47 of 47	ENSP00000384202.1	C9JE98

Frequencies

GnomAD3 genomes AF: 0.00000687 AC: 1 AN: 145638 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1197020 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 583040

African (AFR) AF: 0.00 AC: 0 AN: 23944

American (AMR) AF: 0.00 AC: 0 AN: 13756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17054

East Asian (EAS) AF: 0.00 AC: 0 AN: 26472

South Asian (SAS) AF: 0.00 AC: 0 AN: 51628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 972770

Other (OTH) AF: 0.00 AC: 0 AN: 47464

GnomAD4 genome AF: 0.00000687 AC: 1 AN: 145638 Hom.: 0 Cov.: 30 AF XY: 0.0000142 AC XY: 1 AN XY: 70508

African (AFR) AF: 0.0000251 AC: 1 AN: 39786

American (AMR) AF: 0.00 AC: 0 AN: 13856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 4818

South Asian (SAS) AF: 0.00 AC: 0 AN: 4574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66644

Other (OTH) AF: 0.00 AC: 0 AN: 2002

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.82	T
PhyloP100		9.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.53
Sift	Benign	0.076	T
Sift4G	Benign	0.074	T
Vest4		0.71
MVP		0.79
MPC		0.71
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.54
gMVP		0.53
Mutation Taster		=60/40	polymorphism

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: rs2034543440; hg19: chr12-124809992;