8-70126986-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_006540.4(NCOA2):c.3743G>A(p.Arg1248Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: NCOA2 NM_006540.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.65

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NCOA2
• BP4: Computational evidence support a benign effect (MetaRNN=0.2679975).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA2	NM_006540.4	c.3743G>A	p.Arg1248Gln	missense_variant	19/23	ENST00000452400.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA2	ENST00000452400.7	c.3743G>A	p.Arg1248Gln	missense_variant	19/23	1	NM_006540.4	P1
NCOA2	ENST00000518363.2	c.1121G>A	p.Arg374Gln	missense_variant	7/11	2
NCOA2	ENST00000521239.1	n.186G>A		non_coding_transcript_exon_variant	3/3	4
NCOA2	ENST00000518287.6	c.*700G>A		3_prime_UTR_variant, NMD_transcript_variant	18/21	5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000604 AC: 15 AN: 248516 Hom.: 0 AF XY: 0.0000445 AC XY: 6 AN XY: 134796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461414 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 726940

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74340

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000496 AC: 6

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

Dec 30, 2023

The c.3743G>A (p.R1248Q) alteration is located in exon 19 (coding exon 17) of the NCOA2 gene. This alteration results from a G to A substitution at nucleotide position 3743, causing the arginine (R) at amino acid position 1248 to be replaced by a glutamine (Q). 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	Benign	0.32
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.20
Sift	Benign	0.21	T
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.21		Loss of MoRF binding (P = 0.1239);
MVP		0.47
MPC		0.47
ClinPred		0.85	D
GERP RS		6.0
Varity_R		0.26
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs753507017; hg19: chr8-71039221; COSMIC: COSV51218384;