chr8-70126830-G-T

Variant names:

• chr8-70126830-G-T
• NM_006540.4:c.3899C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006540.4(NCOA2):​c.3899C>A​(p.Pro1300Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCOA2 NM_006540.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

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.3899C>A	p.Pro1300Gln	missense	Exon 19 of 23	NP_006531.1	Q15596
	NCOA2	NM_001321703.2		c.3899C>A	p.Pro1300Gln	missense	Exon 19 of 23	NP_001308632.1	Q15596
	NCOA2	NM_001321707.2		c.3899C>A	p.Pro1300Gln	missense	Exon 19 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.3899C>A	p.Pro1300Gln	missense	Exon 19 of 23	ENSP00000399968.2	Q15596
	NCOA2	ENST00000892895.1		c.3899C>A	p.Pro1300Gln	missense	Exon 20 of 24	ENSP00000562954.1
	NCOA2	ENST00000892896.1		c.3899C>A	p.Pro1300Gln	missense	Exon 19 of 23	ENSP00000562955.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	0.21
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.49		Loss of glycosylation at P1300 (P = 0.0719)
MVP		0.51
MPC		0.44
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.48
gMVP		0.51
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

hg19: chr8-71039065;