8-70128448-A-G

Position:

• chr8-70128448-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006540.4(NCOA2):​c.3666T>C​(p.Pro1222=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,612,312 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: NCOA2 NM_006540.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.558

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 8-70128448-A-G is Benign according to our data. Variant chr8-70128448-A-G is described in ClinVar as [Benign]. Clinvar id is 783528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.558 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1815/152358) while in subpopulation AFR AF= 0.0416 (1730/41572). AF 95% confidence interval is 0.04. There are 49 homozygotes in gnomad4. There are 881 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1815 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCOA2	NM_006540.4	c.3666T>C	p.Pro1222=	synonymous_variant	18/23	ENST00000452400.7	NP_006531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCOA2	ENST00000452400.7	c.3666T>C	p.Pro1222=	synonymous_variant	18/23	1	NM_006540.4	ENSP00000399968	P1
NCOA2	ENST00000518363.2	c.1044T>C	p.Pro348=	synonymous_variant	6/11	2		ENSP00000429132
NCOA2	ENST00000521239.1	n.109T>C		non_coding_transcript_exon_variant	2/3	4
NCOA2	ENST00000518287.6	c.*623T>C		3_prime_UTR_variant, NMD_transcript_variant	17/21	5		ENSP00000430148

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1814 AN: 152240 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00281 AC: 692 AN: 246174 Hom.: 14 AF XY: 0.00219 AC XY: 293 AN XY: 133522

Gnomad AFR exome AF: 0.0406

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000984

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00118 AC: 1720 AN: 1459954 Hom.: 34 Cov.: 31 AF XY: 0.000990 AC XY: 719 AN XY: 726088

Gnomad4 AFR exome AF: 0.0420

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.0119 AC: 1815 AN: 152358 Hom.: 49 Cov.: 32 AF XY: 0.0118 AC XY: 881 AN XY: 74504

Gnomad4 AFR AF: 0.0416

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00806 Hom.: 10

Bravo AF: 0.0135

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.6
DANN	Benign	0.70

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: rs2228592; hg19: chr8-71040683;