chr8-70131999-C-G

Variant names:

• chr8-70131999-C-G
• NM_006540.4:c.3162G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006540.4(NCOA2):​c.3162G>C​(p.Gln1054His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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: 0.0160

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15500075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA2	NM_006540.4	c.3162G>C	p.Gln1054His	missense_variant	Exon 16 of 23	ENST00000452400.7	NP_006531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOA2	ENST00000452400.7	c.3162G>C	p.Gln1054His	missense_variant	Exon 16 of 23	1	NM_006540.4	ENSP00000399968.2
NCOA2	ENST00000518363.2	c.537G>C	p.Gln179His	missense_variant	Exon 4 of 11	2		ENSP00000429132.2
NCOA2	ENST00000518287.6	n.*119G>C		non_coding_transcript_exon_variant	Exon 15 of 21	5		ENSP00000430148.2
NCOA2	ENST00000518287.6	n.*119G>C		3_prime_UTR_variant	Exon 15 of 21	5		ENSP00000430148.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3162G>C (p.Q1054H) alteration is located in exon 16 (coding exon 14) of the NCOA2 gene. This alteration results from a G to C substitution at nucleotide position 3162, causing the glutamine (Q) at amino acid position 1054 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.047
Sift	Benign	0.31	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.15		Gain of catalytic residue at Q1054 (P = 0.0804);
MVP		0.50
MPC		0.12
ClinPred		0.42	T
GERP RS		-0.24
Varity_R		0.063
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-71044234;