3-186150103-C-T

Variant names:

• chr3-186150103-C-T
• rs201727536
• NM_001346.3:c.2363G>A

Variant summary

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

The NM_001346.3(DGKG):​c.2363G>A​(p.Arg788His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,178 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (2 hom.)
• Consequence: DGKG NM_001346.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

Genes affected

DGKG (HGNC:2853): (diacylglycerol kinase gamma) This gene encodes an enzyme that is a member of the type I subfamily of diacylglycerol kinases, which are involved in lipid metabolism. These enzymes generate phosphatidic acid by catalyzing the phosphorylation of diacylglycerol, a fundamental lipid second messenger that activates numerous proteins, including protein kinase C isoforms, Ras guanyl nucleotide-releasing proteins and some transient receptor potential channels. Diacylglycerol kinase gamma has been implicated in cell cycle regulation and in the negative regulation of macrophage differentiation in leukemia cells. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2533118).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DGKG	NM_001346.3	c.2363G>A	p.Arg788His	missense_variant	Exon 25 of 25	ENST00000265022.8	NP_001337.2
DGKG	NM_001080744.2	c.2288G>A	p.Arg763His	missense_variant	Exon 24 of 24		NP_001074213.1
DGKG	NM_001080745.2	c.2246G>A	p.Arg749His	missense_variant	Exon 24 of 24		NP_001074214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DGKG	ENST00000265022.8	c.2363G>A	p.Arg788His	missense_variant	Exon 25 of 25	1	NM_001346.3	ENSP00000265022.3

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000168 AC: 42 AN: 249930 Hom.: 2 AF XY: 0.000178 AC XY: 24 AN XY: 135032

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000144 AC: 210 AN: 1460996 Hom.: 2 Cov.: 33 AF XY: 0.000131 AC XY: 95 AN XY: 726716

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000221

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74336

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000274 Hom.: 1

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2363G>A (p.R788H) alteration is located in exon 25 (coding exon 24) of the DGKG gene. This alteration results from a G to A substitution at nucleotide position 2363, causing the arginine (R) at amino acid position 788 to be replaced by a histidine (H). 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	0.14
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.028	D;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.23
MVP		0.91
MPC		0.089
ClinPred		0.086	T
GERP RS		5.2
Varity_R		0.14
gMVP		0.37

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: rs201727536; hg19: chr3-185867892; COSMIC: COSV53962058; COSMIC: COSV53962058;