rs61754973

Variant names:

• chr8-70121331-T-C
• rs61754973
• NM_006540.4:c.4354A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006540.4(NCOA2):​c.4354A>G​(p.Met1452Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,613,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (0 hom.)
• Consequence: NCOA2 NM_006540.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34
• Publications: 6 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030479759).
• BS2: High AC in GnomAd4 at 92 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006540.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOA2	NM_006540.4	MANE Select	c.4354A>G	p.Met1452Val	missense	Exon 22 of 23	NP_006531.1	Q15596
	NCOA2	NM_001321703.2		c.4354A>G	p.Met1452Val	missense	Exon 22 of 23	NP_001308632.1	Q15596
	NCOA2	NM_001321707.2		c.4354A>G	p.Met1452Val	missense	Exon 22 of 23	NP_001308636.1	Q15596

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOA2	ENST00000452400.7	TSL:1 MANE Select	c.4354A>G	p.Met1452Val	missense	Exon 22 of 23	ENSP00000399968.2	Q15596
	NCOA2	ENST00000892895.1		c.4354A>G	p.Met1452Val	missense	Exon 23 of 24	ENSP00000562954.1
	NCOA2	ENST00000892896.1		c.4354A>G	p.Met1452Val	missense	Exon 22 of 23	ENSP00000562955.1

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000484 AC: 120 AN: 248126 AF XY: 0.000483

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000941

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000967 AC: 1413 AN: 1460814 Hom.: 0 Cov.: 30 AF XY: 0.000910 AC XY: 661 AN XY: 726562

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0000672 AC: 3 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85960

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00119 AC: 1320 AN: 1111468

Other (OTH) AF: 0.00113 AC: 68 AN: 60346

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74500

African (AFR) AF: 0.000192 AC: 8 AN: 41590

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68030

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.000567

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000968 AC: 8

ExAC AF: 0.000513 AC: 62

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000892

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.058
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.063
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.17	T
Polyphen		0.41	B
Vest4		0.45
MVP		0.26
MPC		0.13
ClinPred		0.044	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.36
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs61754973; hg19: chr8-71033566; COSMIC: COSV99069501;