8-70123885-T-C

Variant names:

• chr8-70123885-T-C
• rs1214618193
• NM_006540.4:c.4292A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006540.4(NCOA2):​c.4292A>G​(p.Gln1431Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000689 in 1,452,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NCOA2 NM_006540.4 missense, splice_region
• Scores: Splicing: ADA: 0.9918
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77
• Publications: 0 publications found

Genes affected

NCOA2 (HGNC:7669): (nuclear receptor coactivator 2) The protein encoded by this gene functions as a transcriptional coactivator for nuclear hormone receptors, including steroid, thyroid, retinoid, and vitamin D receptors. The encoded protein acts as an intermediary factor for the ligand-dependent activity of these nuclear receptors, which regulate their target genes upon binding of cognate response elements. This gene has been found to be involved in translocations that result in fusions with other genes in various cancers, including the lysine acetyltransferase 6A (KAT6A) gene in acute myeloid leukemia, the ETS variant 6 (ETV6) gene in acute lymphoblastic leukemia, and the hes related family bHLH transcription factor with YRPW motif 1 (HEY1) gene in mesenchymal chondrosarcoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA2	NM_006540.4	c.4292A>G	p.Gln1431Arg	missense_variant, splice_region_variant	Exon 21 of 23	ENST00000452400.7	NP_006531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOA2	ENST00000452400.7	c.4292A>G	p.Gln1431Arg	missense_variant, splice_region_variant	Exon 21 of 23	1	NM_006540.4	ENSP00000399968.2
NCOA2	ENST00000518363.2	c.1667A>G	p.Gln556Arg	missense_variant, splice_region_variant	Exon 9 of 11	2		ENSP00000429132.2
NCOA2	ENST00000518287.6	n.*1249A>G		non_coding_transcript_exon_variant	Exon 20 of 21	5		ENSP00000430148.2
NCOA2	ENST00000518287.6	n.*1249A>G		3_prime_UTR_variant	Exon 20 of 21	5		ENSP00000430148.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452098 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720818

African (AFR) AF: 0.0000300 AC: 1 AN: 33298

American (AMR) AF: 0.00 AC: 0 AN: 44130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.00 AC: 0 AN: 84718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105642

Other (OTH) AF: 0.00 AC: 0 AN: 59940

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4292A>G (p.Q1431R) alteration is located in exon 21 (coding exon 19) of the NCOA2 gene. This alteration results from a A to G substitution at nucleotide position 4292, causing the glutamine (Q) at amino acid position 1431 to be replaced by an arginine (R). 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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.29		Gain of phosphorylation at S1426 (P = 0.1346);
MVP		0.81
MPC		0.58
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.81
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
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: rs1214618193; hg19: chr8-71036120;