2-233354616-C-A

Variant names:

• chr2-233354616-C-A
• rs750944437
• NM_152879.3:c.98C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152879.3(DGKD):​c.98C>A​(p.Pro33His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000102 in 982,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P33S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: DGKD NM_152879.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• Publications: 0 publications found

Genes affected

DGKD (HGNC:2851): (diacylglycerol kinase delta) This gene encodes a cytoplasmic enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. Diacylglycerol and phosphatidic acid are two lipids that act as second messengers in signaling cascades. Their cellular concentrations are regulated by the encoded protein, and so it is thought to play an important role in cellular signal transduction. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25404054).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152879.3. 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
	DGKD	NM_152879.3	MANE Select	c.98C>A	p.Pro33His	missense	Exon 1 of 30	NP_690618.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGKD	ENST00000264057.7	TSL:1 MANE Select	c.98C>A	p.Pro33His	missense	Exon 1 of 30	ENSP00000264057.2	Q16760-1
	DGKD	ENST00000963810.1		c.98C>A	p.Pro33His	missense	Exon 1 of 31	ENSP00000633869.1
	DGKD	ENST00000963809.1		c.98C>A	p.Pro33His	missense	Exon 1 of 31	ENSP00000633868.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000102 AC: 1 AN: 982912 Hom.: 0 Cov.: 31 AF XY: 0.00000209 AC XY: 1 AN XY: 478084

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19228

American (AMR) AF: 0.00 AC: 0 AN: 16288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12102

East Asian (EAS) AF: 0.00 AC: 0 AN: 6490

South Asian (SAS) AF: 0.00 AC: 0 AN: 47378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2626

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838986

Other (OTH) AF: 0.00 AC: 0 AN: 33354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.20	N
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.46	N
PhyloP100		-0.030
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.097
MutPred		0.18		Loss of loop (P = 0.0128)
MVP		0.74
MPC		0.58
ClinPred		0.83	D
GERP RS		1.3
PromoterAI		0.082	Neutral
Varity_R		0.17
gMVP		0.42
Mutation Taster		=77/23	polymorphism

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

dbSNP: rs750944437; hg19: chr2-234263262;