Genetic Variant NCOA2:p.Ala1199Thr (chr8-70128710-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006540.4(NCOA2):c.3595G>A(p.Ala1199Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1199S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NCOA2
NM_006540.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.59

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31466246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA2	NM_006540.4 link	c.3595G>A	p.Ala1199Thr	missense_variant	Exon 17 of 23	ENST00000452400.7	NP_006531.1	Q15596

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOA2	ENST00000452400.7 link	c.3595G>A	p.Ala1199Thr	missense_variant	Exon 17 of 23	1	NM_006540.4	ENSP00000399968.2		Q15596

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248506

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461134

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726888

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111790

Other (OTH)

AF:

0.00

AC:

AN:

60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000626), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0094

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.2

PhyloP100

5.6

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.2

REVEL

Benign

0.12

Sift

Benign

0.18

Sift4G

Uncertain

0.0060

Polyphen

0.57

Vest4

0.45

MutPred

0.14

Gain of phosphorylation at A1199 (P = 0.0845);

MVP

0.33

MPC

0.25

ClinPred

0.64

GERP RS

5.9

Varity_R

0.15

gMVP

0.49

Mutation Taster

=69/31

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over