8-70128911-C-T

Position:

• chr8-70128911-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.96

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 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/exons	MANE	Protein	UniProt
NCOA2	NM_006540.4	c.3394G>A	p.Val1132Ile	missense_variant	17/23	ENST00000452400.7	NP_006531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCOA2	ENST00000452400.7	c.3394G>A	p.Val1132Ile	missense_variant	17/23	1	NM_006540.4	ENSP00000399968	P1
NCOA2	ENST00000518363.2	c.772G>A	p.Val258Ile	missense_variant	5/11	2		ENSP00000429132
NCOA2	ENST00000518287.6	c.*351G>A		3_prime_UTR_variant, NMD_transcript_variant	16/21	5		ENSP00000430148

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152148 Hom.: 2 Cov.: 32

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.: 2 AF XY: 0.000866 AC XY: 116 AN XY: 133910

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.: 3 Cov.: 31 AF XY: 0.000557 AC XY: 405 AN XY: 726484

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.: 2 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74442

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.: 0

Bravo AF: 0.00306

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00677 AC: 27

ESP6500EA AF: 0.000360 AC: 3

ExAC AF: 0.00101 AC: 122

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.70	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.042
Sift	Benign	0.043	D
Sift4G	Benign	0.26	T
Polyphen		0.18	B
Vest4		0.21
MVP		0.30
MPC		0.11
ClinPred		0.014	T
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

Other links and lift over

dbSNP: rs115177449; hg19: chr8-71041146;