8-70124824-T-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_006540.4(NCOA2):c.3958A>T(p.Thr1320Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,456,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NCOA2
NM_006540.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

Variant links:

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]

NCOA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, NCOA2

BP4

Computational evidence support a benign effect (MetaRNN=0.10636166).

BS2

High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA2	NM_006540.4 linkuse as main transcript	c.3958A>T	p.Thr1320Ser	missense_variant	20/23	ENST00000452400.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NCOA2	ENST00000452400.7 linkuse as main transcript	c.3958A>T	p.Thr1320Ser	missense_variant	20/23	1	NM_006540.4	P1
NCOA2	ENST00000518363.2 linkuse as main transcript	c.1336A>T	p.Thr446Ser	missense_variant	8/11	2
NCOA2	ENST00000518287.6 linkuse as main transcript	c.*915A>T		3_prime_UTR_variant, NMD_transcript_variant	19/21	5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

148968

Hom.:

Cov.:

FAILED QC

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:

0.0000999

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

244250

Hom.:

AF XY:

0.0000301

AC XY:

AN XY:

132706

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000227

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1456830

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000671

AC:

AN:

148968

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72488

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000999

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.3958A>T (p.T1320S) alteration is located in exon 20 (coding exon 18) of the NCOA2 gene. This alteration results from a A to T substitution at nucleotide position 3958, causing the threonine (T) at amino acid position 1320 to be replaced by a serine (S). 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

0.087

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.59

Cadd

Benign

Dann

Benign

0.39

DEOGEN2

Benign

0.062

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.61

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.012

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.050

MutationTaster

Benign

0.92

N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

0.98

REVEL

Benign

0.033

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.47

Vest4

0.31

MutPred

0.28

Gain of glycosylation at T1320 (P = 0.0644);

MVP

0.36

MPC

0.27

ClinPred

0.085

GERP RS

0.83

Varity_R

0.037

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over