rs368000611

Variant names:

• chr8-70124796-C-T
• rs368000611
• NM_006540.4:c.3986G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_006540.4(NCOA2):​c.3986G>A​(p.Arg1329Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,612,988 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: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NCOA2 NM_006540.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA2	NM_006540.4	c.3986G>A	p.Arg1329Gln	missense_variant	Exon 20 of 23	ENST00000452400.7	NP_006531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOA2	ENST00000452400.7	c.3986G>A	p.Arg1329Gln	missense_variant	Exon 20 of 23	1	NM_006540.4	ENSP00000399968.2
NCOA2	ENST00000518363.2	c.1361G>A	p.Arg454Gln	missense_variant	Exon 8 of 11	2		ENSP00000429132.2
NCOA2	ENST00000518287.6	n.*943G>A		non_coding_transcript_exon_variant	Exon 19 of 21	5		ENSP00000430148.2
NCOA2	ENST00000518287.6	n.*943G>A		3_prime_UTR_variant	Exon 19 of 21	5		ENSP00000430148.2

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151562 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000955

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248906 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461426 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727018

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.0000224 AC: 1 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111728

Other (OTH) AF: 0.0000663 AC: 4 AN: 60350

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151562 Hom.: 0 Cov.: 32 AF XY: 0.0000406 AC XY: 3 AN XY: 73970

African (AFR) AF: 0.00 AC: 0 AN: 41230

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.0000955 AC: 1 AN: 10466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000860 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3986G>A (p.R1329Q) alteration is located in exon 20 (coding exon 18) of the NCOA2 gene. This alteration results from a G to A substitution at nucleotide position 3986, causing the arginine (R) at amino acid position 1329 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	0.26
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.33
Sift	Benign	0.54	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.87
MVP		0.62
MPC		0.62
ClinPred		0.72	D
GERP RS		5.8
Varity_R		0.15
gMVP		0.46
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs368000611; hg19: chr8-71037031; COSMIC: COSV51218918; COSMIC: COSV51218918;