rs76583617

Variant names:

• chr11-46379558-C-G
• rs76583617
• NM_001199267.2:c.2660C>G
• DGKZ p.Thr887Arg

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 431729.
• BS2: High AC in GnomAd4 at 652 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199267.2. 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
	DGKZ	NM_001199267.2	MANE Select	c.2660C>G	p.Thr887Arg	missense	Exon 30 of 31	NP_001186196.1	Q13574-2
	DGKZ	NM_001105540.2		c.3227C>G	p.Thr1076Arg	missense	Exon 31 of 32	NP_001099010.1	Q13574-1
	DGKZ	NM_201532.3		c.2711C>G	p.Thr904Arg	missense	Exon 30 of 31	NP_963290.1	Q13574-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGKZ	ENST00000456247.7	TSL:1 MANE Select	c.2660C>G	p.Thr887Arg	missense	Exon 30 of 31	ENSP00000395684.2	Q13574-2
	DGKZ	ENST00000454345.6	TSL:1	c.3227C>G	p.Thr1076Arg	missense	Exon 31 of 32	ENSP00000412178.1	Q13574-1
	DGKZ	ENST00000527911.5	TSL:1	c.2678C>G	p.Thr893Arg	missense	Exon 30 of 31	ENSP00000436291.1	Q13574-5

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

GnomAD2 exomes AF: 0.00360 AC: 856 AN: 237920 AF XY: 0.00368

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 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

African (AFR) AF: 0.000928 AC: 31 AN: 33416

American (AMR) AF: 0.00308 AC: 136 AN: 44202

Ashkenazi Jewish (ASJ) AF: 0.00502 AC: 130 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000817 AC: 7 AN: 85650

European-Finnish (FIN) AF: 0.00197 AC: 102 AN: 51650

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 0.00723 AC: 8029 AN: 1110310

Other (OTH) AF: 0.00528 AC: 318 AN: 60180

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

African (AFR) AF: 0.00137 AC: 57 AN: 41580

American (AMR) AF: 0.00451 AC: 69 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00716 AC: 487 AN: 68036

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00539 Hom.: 0

Bravo AF: 0.00437

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	atypical cerebral palsy (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.27	N
PhyloP100		4.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.57
Sift	Benign	0.20	T
Sift4G	Benign	0.24	T
Varity_R		0.50
gMVP		0.48
Mutation Taster		=87/13	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs76583617;

hg19: chr11-46401108;

COSMIC: COSV58991184;

COSMIC: COSV58991184;