21-36200399-A-G

Position:

• chr21-36200399-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001320714.2(DOP1B):​c.389A>G​(p.Glu130Gly) 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. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOP1B NM_001320714.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.75

Genes affected

DOP1B (HGNC:1291): (DOP1 leucine zipper like protein B) Involved in cognition. Located in early endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

DOP1B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOP1B	NM_001320714.2	c.389A>G	p.Glu130Gly	missense_variant	4/37	ENST00000691173.1	NP_001307643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOP1B	ENST00000691173.1	c.389A>G	p.Glu130Gly	missense_variant	4/37		NM_001320714.2	ENSP00000509598.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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 14, 2024

The c.389A>G (p.E130G) alteration is located in exon 4 (coding exon 3) of the DOPEY2 gene. This alteration results from a A to G substitution at nucleotide position 389, causing the glutamic acid (E) at amino acid position 130 to be replaced by a glycine (G). 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	.;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.4	.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.65		Loss of ubiquitination at K131 (P = 0.0811);Loss of ubiquitination at K131 (P = 0.0811);
MVP		0.51
MPC		0.79
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.84
gMVP		0.65

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: chr21-37572697;