chr3-186164992-C-T

Variant names:

• chr3-186164992-C-T
• NM_001346.3:c.2122G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001346.3(DGKG):​c.2122G>A​(p.Val708Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.000016 (0 hom.)
• Consequence: DGKG NM_001346.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGKG	NM_001346.3	MANE Select	c.2122G>A	p.Val708Met	missense	Exon 23 of 25	NP_001337.2	P49619-1
	DGKG	NM_001080744.2		c.2047G>A	p.Val683Met	missense	Exon 22 of 24	NP_001074213.1	P49619-2
	DGKG	NM_001080745.2		c.2005G>A	p.Val669Met	missense	Exon 22 of 24	NP_001074214.1	P49619-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGKG	ENST00000265022.8	TSL:1 MANE Select	c.2122G>A	p.Val708Met	missense	Exon 23 of 25	ENSP00000265022.3	P49619-1
	DGKG	ENST00000344484.8	TSL:1	c.2047G>A	p.Val683Met	missense	Exon 22 of 24	ENSP00000339777.4	P49619-2
	DGKG	ENST00000480809.5	TSL:1	n.2479G>A		non_coding_transcript_exon	Exon 23 of 24

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461576 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727104

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111930

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.70		Loss of sheet (P = 0.1398)
MVP		0.60
MPC		0.43
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.67
Mutation Taster		=31/69	disease causing

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

Other links and lift over

hg19: chr3-185882781;