chr17-18088069-C-T

Position:

• chr17-18088069-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001388.5(DRG2):​c.46C>T​(p.Arg16Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DRG2 NM_001388.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56

Genes affected

DRG2 (HGNC:3030): (developmentally regulated GTP binding protein 2) This gene encodes a GTP-binding protein known to function in the regulation of cell growth and differentiation. Read-through transcripts containing this gene and a downstream gene have been identified, but they are not thought to encode a fusion protein. This gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DRG2	NM_001388.5	c.46C>T	p.Arg16Trp	missense_variant	1/13	ENST00000225729.8
DRG2	NM_001330144.2	c.46C>T	p.Arg16Trp	missense_variant	1/13
DRG2	XM_005256499.4	c.46C>T	p.Arg16Trp	missense_variant	1/13
DRG2	XM_011523704.3	c.46C>T	p.Arg16Trp	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRG2	ENST00000225729.8	c.46C>T	p.Arg16Trp	missense_variant	1/13	1	NM_001388.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395966 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 688496

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Oct 20, 2023

The c.46C>T (p.R16W) alteration is located in exon 1 (coding exon 1) of the DRG2 gene. This alteration results from a C to T substitution at nucleotide position 46, causing the arginine (R) at amino acid position 16 to be replaced by a tryptophan (W). 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	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T;T;T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.8	H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.3	D;D;.;.;.
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.69
MutPred		0.51		Loss of disorder (P = 0.0035);Loss of disorder (P = 0.0035);Loss of disorder (P = 0.0035);Loss of disorder (P = 0.0035);Loss of disorder (P = 0.0035);
MVP		0.52
MPC		1.5
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.60

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: chr17-17991383;