12-124325588-G-T

Variant names:

• chr12-124325588-G-T
• rs189013704
• NM_006312.6:c.7364-5C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006312.6(NCOR2):​c.7364-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000892 in 1,121,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: NCOR2 NM_006312.6 splice_region, intron
• Scores: Splicing: ADA: 0.7152
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.562
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.7364-5C>A		splice_region intron	N/A	NP_006303.4	Q9Y618-1
	NCOR2	NM_001206654.2		c.7334-5C>A		splice_region intron	N/A	NP_001193583.1	C9J0Q5
	NCOR2	NM_001077261.4		c.7196-5C>A		splice_region intron	N/A	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.7364-5C>A		splice_region intron	N/A	ENSP00000384018.1	Q9Y618-1
	NCOR2	ENST00000429285.6	TSL:1	c.7334-5C>A		splice_region intron	N/A	ENSP00000400281.2	C9J0Q5
	NCOR2	ENST00000404621.5	TSL:1	c.7196-5C>A		splice_region intron	N/A	ENSP00000384202.1	C9JE98

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 8.92e-7 AC: 1 AN: 1121538 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 533070

African (AFR) AF: 0.00 AC: 0 AN: 24208

American (AMR) AF: 0.00 AC: 0 AN: 8772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14644

East Asian (EAS) AF: 0.00 AC: 0 AN: 28320

South Asian (SAS) AF: 0.00 AC: 0 AN: 27228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4050

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 932494

Other (OTH) AF: 0.00 AC: 0 AN: 44828

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	16
DANN	Benign	0.46
PhyloP100		-0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.72
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.79		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs189013704; hg19: chr12-124810134;