14-29577455-T-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP3 BS2

The NM_002742.3(PRKD1):c.2522A>T(p.Asp841Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRKD1 NM_002742.3 missense, splice_region
• Scores: Splicing: ADA: 0.9205
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

PRKD1 (HGNC:9407): (protein kinase D1) The protein encoded by this gene is a serine/threonine protein kinase involved in many cellular processes, including Golgi body membrane integrity and transport, cell migration and differentiation, MAPK8/JNK1 and Ras pathway signaling, MAPK1/3 (ERK1/2) pathway signaling, cell survival, and regulation of cell shape and adhesion. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKD1	NM_002742.3	c.2522A>T	p.Asp841Val	missense_variant, splice_region_variant	18/18	ENST00000331968.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKD1	ENST00000331968.11	c.2522A>T	p.Asp841Val	missense_variant, splice_region_variant	18/18	1	NM_002742.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250380 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460994 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

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

Feb 13, 2024

The c.2522A>T (p.D841V) alteration is located in exon 18 (coding exon 18) of the PRKD1 gene. This alteration results from a A to T substitution at nucleotide position 2522, causing the aspartic acid (D) at amino acid position 841 to be replaced by a valine (V). 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	0.73
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;D;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.91
MutPred		0.50		Gain of MoRF binding (P = 0.0445);Gain of MoRF binding (P = 0.0445);.;
MVP		0.94
MPC		1.1
ClinPred		0.93	D
GERP RS		6.2
Varity_R		0.84
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.82
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: rs369158333; hg19: chr14-30046661;