12-124325588-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006312.6(NCOR2):c.7364-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,273,698 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: NCOR2 NM_006312.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000007971
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.562

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-124325588-G-A is Benign according to our data. Variant chr12-124325588-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3052029.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOR2	NM_006312.6	c.7364-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000405201.6
NCOR2	NM_001077261.4	c.7196-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
NCOR2	NM_001206654.2	c.7334-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOR2	ENST00000405201.6	c.7364-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006312.6	P4

Frequencies

GnomAD3 genomes AF: 0.000579 AC: 88 AN: 152048 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000377 AC: 11 AN: 29182 Hom.: 0 AF XY: 0.000497 AC XY: 7 AN XY: 14072

Gnomad AFR exome AF: 0.000362

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000986

Gnomad FIN exome AF: 0.000393

Gnomad NFE exome AF: 0.000410

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00117 AC: 1309 AN: 1121532 Hom.: 0 Cov.: 37 AF XY: 0.00120 AC XY: 638 AN XY: 533068

Gnomad4 AFR exome AF: 0.000454

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.000959

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152166 Hom.: 1 Cov.: 30 AF XY: 0.000470 AC XY: 35 AN XY: 74398

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000868

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000651 Hom.: 0

Bravo AF: 0.000461

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NCOR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.83
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000080
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs189013704; hg19: chr12-124810134;