chr2-233354552-C-A

Position:

• chr2-233354552-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_152879.3(DGKD):​c.34C>A​(p.Pro12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,023,558 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 30)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: DGKD NM_152879.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.121

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

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08562681).
• BP6: Variant 2-233354552-C-A is Benign according to our data. Variant chr2-233354552-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 734116.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGKD	NM_152879.3	c.34C>A	p.Pro12Thr	missense_variant	1/30	ENST00000264057.7	NP_690618.2
DGKD	XM_047446097.1	c.34C>A	p.Pro12Thr	missense_variant	1/29		XP_047302053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGKD	ENST00000264057.7	c.34C>A	p.Pro12Thr	missense_variant	1/30	1	NM_152879.3	ENSP00000264057.2
DGKD	ENST00000427930.5	c.34C>A	p.Pro12Thr	missense_variant	1/4	5		ENSP00000407938.1
DGKD	ENST00000442524.4	c.-21C>A		upstream_gene_variant		3		ENSP00000485047.1

Frequencies

GnomAD3 genomes AF: 0.000885 AC: 129 AN: 145716 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000911 AC: 80 AN: 877820 Hom.: 0 Cov.: 31 AF XY: 0.0000867 AC XY: 36 AN XY: 415264

Gnomad4 AFR exome AF: 0.00441

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: 0.00000127

Gnomad4 OTH exome AF: 0.000207

GnomAD4 genome AF: 0.000885 AC: 129 AN: 145738 Hom.: 1 Cov.: 30 AF XY: 0.000875 AC XY: 62 AN XY: 70870

Gnomad4 AFR AF: 0.00304

Gnomad4 AMR AF: 0.000340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000971

ExAC AF: 0.000107 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.34C>A (p.P12T) alteration is located in exon 1 (coding exon 1) of the DGKD gene. This alteration results from a C to A substitution at nucleotide position 34, causing the proline (P) at amino acid position 12 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.074	T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.43	N;N
REVEL	Benign	0.18
Sift	Benign	0.067	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.015	B;.
Vest4		0.14
MutPred		0.26		Gain of phosphorylation at P12 (P = 1e-04);Gain of phosphorylation at P12 (P = 1e-04);
MVP		0.57
MPC		0.55
ClinPred		0.086	T
GERP RS		-1.0
Varity_R		0.075
gMVP		0.41

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: rs747669327; hg19: chr2-234263198;