20-63590343-T-G

Position:

• chr20-63590343-T-G

Variant summary

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

The NM_012384.5(GMEB2):​c.1339A>C​(p.Ile447Leu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: GMEB2 NM_012384.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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 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=0.07721147).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GMEB2	NM_012384.5	c.1339A>C	p.Ile447Leu	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.1339A>C	p.Ile447Leu	missense_variant	10/10	1	NM_012384.5	ENSP00000359094.1
GMEB2	ENST00000266068.5	c.1339A>C	p.Ile447Leu	missense_variant	9/9	2		ENSP00000266068.1
GMEB2	ENST00000370069.5	c.1186A>C	p.Ile396Leu	missense_variant	8/8	5		ENSP00000359086.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

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

Jan 11, 2023

The c.1339A>C (p.I447L) alteration is located in exon 10 (coding exon 9) of the GMEB2 gene. This alteration results from a A to C substitution at nucleotide position 1339, causing the isoleucine (I) at amino acid position 447 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.031	.;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T;.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.077	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Benign	0.050
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.10
MutPred		0.28		.;Loss of catalytic residue at P449 (P = 0.0303);Loss of catalytic residue at P449 (P = 0.0303);
MVP		0.38
MPC		0.59
ClinPred		0.15	T
GERP RS		3.1
Varity_R		0.050
gMVP		0.51

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: chr20-62221696;