chr21-33027211-G-A

Position:

• chr21-33027211-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005806.4(OLIG2):​c.349G>A​(p.Glu117Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OLIG2 NM_005806.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.94

Genes affected

OLIG2 (HGNC:9398): (oligodendrocyte transcription factor 2) This gene encodes a basic helix-loop-helix transcription factor which is expressed in oligodendroglial tumors of the brain. The protein is an essential regulator of ventral neuroectodermal progenitor cell fate. The gene is involved in a chromosomal translocation t(14;21)(q11.2;q22) associated with T-cell acute lymphoblastic leukemia. Its chromosomal location is within a region of chromosome 21 which has been suggested to play a role in learning deficits associated with Down syndrome. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OLIG2	NM_005806.4	c.349G>A	p.Glu117Lys	missense_variant	2/2	ENST00000382357.4
OLIG2	XM_005260908.2	c.349G>A	p.Glu117Lys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OLIG2	ENST00000382357.4	c.349G>A	p.Glu117Lys	missense_variant	2/2	1	NM_005806.4	P1
	ENST00000454622.2	n.201+43693C>T		intron_variant, non_coding_transcript_variant		2
OLIG2	ENST00000333337.3	c.349G>A	p.Glu117Lys	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.86		Gain of methylation at E117 (P = 0.0122);Gain of methylation at E117 (P = 0.0122);
MVP		0.97
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.75
gMVP		1.0

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: rs1270614322; hg19: chr21-34399519;