8-70128448-A-G

Variant names:

• chr8-70128448-A-G
• rs2228592
• NM_006540.4:c.3666T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006540.4(NCOA2):​c.3666T>C​(p.Pro1222Pro) 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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.038).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1815 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA2	NM_006540.4	c.3666T>C	p.Pro1222Pro	synonymous_variant	Exon 18 of 23	ENST00000452400.7	NP_006531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOA2	ENST00000452400.7	c.3666T>C	p.Pro1222Pro	synonymous_variant	Exon 18 of 23	1	NM_006540.4	ENSP00000399968.2

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

GnomAD2 exomes AF: 0.00281 AC: 692 AN: 246174 AF XY: 0.00219

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 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 AC: 1405 AN: 33454

Gnomad4 AMR exome AF: 0.00193 AC: 86 AN: 44462

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26046

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39668

Gnomad4 SAS exome AF: 0.0000466 AC: 4 AN: 85786

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53236

Gnomad4 NFE exome AF: 0.0000297 AC: 33 AN: 1111214

Gnomad4 Remaining exome AF: 0.00293 AC: 177 AN: 60322

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 AC: 0.0416145 AN: 0.0416145

Gnomad4 AMR AF: 0.00392 AC: 0.00391901 AN: 0.00391901

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000587855 AN: 0.0000587855

Gnomad4 OTH AF: 0.00852 AC: 0.00852273 AN: 0.00852273

Alfa AF: 0.00766 Hom.: 12

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.6
DANN	Benign	0.70
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs2228592; hg19: chr8-71040683;