12-124325413-C-A

Position:

• chr12-124325413-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006312.6(NCOR2):​c.7534G>T​(p.Asp2512Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 657,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NCOR2 NM_006312.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCOR2	NM_006312.6	c.7534G>T	p.Asp2512Tyr	missense_variant	49/49	ENST00000405201.6	NP_006303.4
NCOR2	NM_001206654.2	c.7504G>T	p.Asp2502Tyr	missense_variant	48/48		NP_001193583.1
NCOR2	NM_001077261.4	c.7366G>T	p.Asp2456Tyr	missense_variant	48/48		NP_001070729.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCOR2	ENST00000405201.6	c.7534G>T	p.Asp2512Tyr	missense_variant	49/49	1	NM_006312.6	ENSP00000384018.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000152 AC: 1 AN: 657180 Hom.: 0 Cov.: 30 AF XY: 0.00000315 AC XY: 1 AN XY: 317090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.7534G>T (p.D2512Y) alteration is located in exon 49 (coding exon 47) of the NCOR2 gene. This alteration results from a G to T substitution at nucleotide position 7534, causing the aspartic acid (D) at amino acid position 2512 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Benign	0.95
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Benign	-0.35	T
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.5	D;D;.;.;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.84
MVP		0.70
MPC		0.79
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.93
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-124809959;