Genetic Variant NM_006540.4:c.3394G>A (chr8-70128911-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006540.4(NCOA2):c.3394G>A(p.Val1132Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000799 in 1,612,912 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 3 hom. )

Consequence

NCOA2
NM_006540.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.96

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006502062).

BP6

Variant 8-70128911-C-T is Benign according to our data. Variant chr8-70128911-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 720153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 405 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA2	NM_006540.4 link	c.3394G>A	p.Val1132Ile	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.3394G>A	p.Val1132Ile	missense_variant	Exon 17 of 23	1	NM_006540.4	ENSP00000399968.2		Q15596

Frequencies

GnomAD3 genomes

AF:

0.00266

AC:

405

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00727

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00110

AC:

271

AN:

246828

Hom.:

AF XY:

0.000866

AC XY:

116

AN XY:

133910

show subpopulations

Gnomad AFR exome

AF:

0.00765

Gnomad AMR exome

AF:

0.00248

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.000225

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000465

Gnomad OTH exome

AF:

0.00200

GnomAD4 exome

AF:

0.000605

AC:

884

AN:

1460646

Hom.:

Cov.:

AF XY:

0.000557

AC XY:

405

AN XY:

726484

show subpopulations

Gnomad4 AFR exome

AF:

0.00804

Gnomad4 AMR exome

AF:

0.00242

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000342

Gnomad4 OTH exome

AF:

0.00169

GnomAD4 genome

AF:

0.00266

AC:

405

AN:

152266

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00724

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.00306

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00677

AC:

ESP6500EA

AF:

0.000360

AC:

ExAC

AF:

0.00101

AC:

122

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.057

Eigen

Benign

-0.10

Eigen_PC

Benign

0.013

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.80

M_CAP

Benign

0.0076

MetaRNN

Benign

0.0065

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.81

PrimateAI

Benign

0.35

PROVEAN

Benign

0.26

REVEL

Benign

0.042

Sift

Benign

0.043

Sift4G

Benign

0.26

Polyphen

0.18

Vest4

0.21

MVP

0.30

MPC

0.11

ClinPred

0.014

GERP RS

5.0

Varity_R

0.050

gMVP

0.072

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