20-63590100-C-G

Position:

• chr20-63590100-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012384.5(GMEB2):​c.1582G>C​(p.Glu528Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000515 in 1,358,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: GMEB2 NM_012384.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

Genes affected

GMEB2 (HGNC:4371): (glucocorticoid modulatory element binding protein 2) This gene is a member of KDWK gene family. The product of this gene associates with GMEB1 protein, and the complex is essential for parvovirus DNA replication. Study of rat homolog implicates the role of this gene in modulation of transactivation by the glucocorticoid receptor bound to glucocorticoid response elements. This gene appears to use multiple polyadenylation sites. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15056577).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GMEB2	NM_012384.5	c.1582G>C	p.Glu528Gln	missense_variant	10/10	ENST00000370077.2	NP_036516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GMEB2	ENST00000370077.2	c.1582G>C	p.Glu528Gln	missense_variant	10/10	1	NM_012384.5	ENSP00000359094.1
GMEB2	ENST00000266068.5	c.1582G>C	p.Glu528Gln	missense_variant	9/9	2		ENSP00000266068.1
GMEB2	ENST00000370069.5	c.1429G>C	p.Glu477Gln	missense_variant	8/8	5		ENSP00000359086.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000515 AC: 7 AN: 1358506 Hom.: 0 Cov.: 31 AF XY: 0.00000451 AC XY: 3 AN XY: 665230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000659

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2024

The c.1582G>C (p.E528Q) alteration is located in exon 10 (coding exon 9) of the GMEB2 gene. This alteration results from a G to C substitution at nucleotide position 1582, causing the glutamic acid (E) at amino acid position 528 to be replaced by a glutamine (Q). 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	0.072
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	.;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.56	T;.;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	.;L;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.070	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.021	.;B;B
Vest4		0.24
MutPred		0.091		.;Gain of MoRF binding (P = 0.0466);Gain of MoRF binding (P = 0.0466);
MVP		0.57
MPC		0.60
ClinPred		0.87	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-62221453;