rs76583617

Positions:

• chr11-46379558-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001199267.2(DGKZ):​c.2660C>G​(p.Thr887Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00585 in 1,609,084 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (39 hom.)
• Consequence: DGKZ NM_001199267.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 4.07

Genes affected

DGKZ (HGNC:2857): (diacylglycerol kinase zeta) The protein encoded by this gene belongs to the eukaryotic diacylglycerol kinase family. It may attenuate protein kinase C activity by regulating diacylglycerol levels in intracellular signaling cascade and signal transduction. Alternative splicing occurs at this locus and multiple transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Nov 2010]

DGKZ (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0153025985).
• BP6: Variant 11-46379558-C-G is Benign according to our data. Variant chr11-46379558-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431729.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd4 at 652 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGKZ	NM_001199267.2	c.2660C>G	p.Thr887Arg	missense_variant	30/31	ENST00000456247.7	NP_001186196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGKZ	ENST00000456247.7	c.2660C>G	p.Thr887Arg	missense_variant	30/31	1	NM_001199267.2	ENSP00000395684.2

Frequencies

GnomAD3 genomes AF: 0.00429 AC: 653 AN: 152250 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00360 AC: 856 AN: 237920 Hom.: 5 AF XY: 0.00368 AC XY: 478 AN XY: 129872

Gnomad AFR exome AF: 0.000941

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00472

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00618

Gnomad OTH exome AF: 0.00380

GnomAD4 exome AF: 0.00601 AC: 8755 AN: 1456716 Hom.: 39 Cov.: 31 AF XY: 0.00584 AC XY: 4233 AN XY: 724452

Gnomad4 AFR exome AF: 0.000928

Gnomad4 AMR exome AF: 0.00308

Gnomad4 ASJ exome AF: 0.00502

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000817

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.00723

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.00428 AC: 652 AN: 152368 Hom.: 3 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74514

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00716

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00539 Hom.: 0

Bravo AF: 0.00437

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00548 AC: 47

ExAC AF: 0.00336 AC: 405

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	DGKZ: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

atypical cerebral palsy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

TIDEX, University of British Columbia

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;.;.;.;.;.;.;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.27	.;.;.;.;.;.;.;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.20	T;D;T;T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T
Polyphen		0.20, 0.24	.;.;.;.;B;.;.;B
Vest4		0.74
MVP		0.95
MPC		1.2
ClinPred		0.044	T
GERP RS		4.3
Varity_R		0.50
gMVP		0.48

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: rs76583617; hg19: chr11-46401108; COSMIC: COSV58991184; COSMIC: COSV58991184;