13-42127524-G-C

Position:

• chr13-42127524-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_178009.5(DGKH):​c.254G>C​(p.Arg85Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DGKH NM_178009.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

DGKH (HGNC:2854): (diacylglycerol kinase eta) This gene encodes a member of the diacylglycerol kinase (DGK) enzyme family. Members of this family are involved in regulating intracellular concentrations of diacylglycerol and phosphatidic acid. Variation in this gene has been associated with bipolar disorder. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGKH	NM_178009.5	c.254G>C	p.Arg85Pro	missense_variant	2/30	ENST00000337343.9	NP_821077.1
DGKH	NM_001204504.3	c.254G>C	p.Arg85Pro	missense_variant	3/30		NP_001191433.1
DGKH	NM_152910.6	c.254G>C	p.Arg85Pro	missense_variant	2/29		NP_690874.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGKH	ENST00000337343.9	c.254G>C	p.Arg85Pro	missense_variant	2/30	1	NM_178009.5	ENSP00000337572.4
DGKH	ENST00000261491.9	c.254G>C	p.Arg85Pro	missense_variant	2/29	1		ENSP00000261491.4
DGKH	ENST00000379274.6	c.254G>C	p.Arg85Pro	missense_variant	3/30	2		ENSP00000368576.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.254G>C (p.R85P) alteration is located in exon 2 (coding exon 2) of the DGKH gene. This alteration results from a G to C substitution at nucleotide position 254, causing the arginine (R) at amino acid position 85 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	4.1	H;H;H
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.4	.;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	.;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.84
MutPred		0.76		Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);
MVP		0.64
MPC		1.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-42701660;