19-46693973-C-G

Position:

• chr19-46693973-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000291281.9(PRKD2):​c.1478G>C​(p.Gly493Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00165 in 1,613,084 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (19 hom.)
• Consequence: PRKD2 ENST00000291281.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.93

Genes affected

PRKD2 (HGNC:17293): (protein kinase D2) The protein encoded by this gene belongs to the protein kinase D (PKD) family of serine/threonine protein kinases. This kinase can be activated by phorbol esters as well as by gastrin via the cholecystokinin B receptor (CCKBR) in gastric cancer cells. It can bind to diacylglycerol (DAG) in the trans-Golgi network (TGN) and may regulate basolateral membrane protein exit from TGN. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00446558).
• BP6: Variant 19-46693973-C-G is Benign according to our data. Variant chr19-46693973-C-G is described in ClinVar as [Benign]. Clinvar id is 781493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00875 (1333/152330) while in subpopulation AFR AF= 0.0289 (1201/41570). AF 95% confidence interval is 0.0275. There are 19 homozygotes in gnomad4. There are 613 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1333 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKD2	NM_016457.5	c.1478G>C	p.Gly493Ala	missense_variant	10/18	ENST00000291281.9	NP_057541.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKD2	ENST00000291281.9	c.1478G>C	p.Gly493Ala	missense_variant	10/18	1	NM_016457.5	ENSP00000291281	P1

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1331 AN: 152212 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00221 AC: 551 AN: 248964 Hom.: 11 AF XY: 0.00172 AC XY: 232 AN XY: 134874

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000897

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000906 AC: 1323 AN: 1460754 Hom.: 19 Cov.: 31 AF XY: 0.000758 AC XY: 551 AN XY: 726706

Gnomad4 AFR exome AF: 0.0296

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.000881

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.00875 AC: 1333 AN: 152330 Hom.: 19 Cov.: 33 AF XY: 0.00823 AC XY: 613 AN XY: 74478

Gnomad4 AFR AF: 0.0289

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.000601 Hom.: 0

Bravo AF: 0.0103

ESP6500AA AF: 0.0263 AC: 116

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00293 AC: 355

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D;D;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	.;.;D;T;D
MetaRNN	Benign	0.0045	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	.;M;M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.3	.;D;D;.;.
REVEL	Benign	0.21
Sift	Benign	0.032	.;D;D;.;.
Sift4G	Benign	0.092	T;T;T;T;T
Polyphen		0.98	.;D;D;.;.
Vest4		0.20
MVP		0.63
MPC		1.8
ClinPred		0.050	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.82

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: rs80021620; hg19: chr19-47197230;