15-63924827-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014326.5(DAPK2):c.847C>T(p.Pro283Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DAPK2 NM_014326.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.55

Genes affected

DAPK2 (HGNC:2675): (death associated protein kinase 2) This gene encodes a protein that belongs to the serine/threonine protein kinase family. This protein contains a N-terminal protein kinase domain followed by a conserved calmodulin-binding domain with significant similarity to that of death-associated protein kinase 1 (DAPK1), a positive regulator of programmed cell death. Overexpression of this gene was shown to induce cell apoptosis. It uses multiple polyadenylation sites. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAPK2	NM_014326.5	c.847C>T	p.Pro283Ser	missense_variant	9/12	ENST00000457488.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAPK2	ENST00000457488.6	c.847C>T	p.Pro283Ser	missense_variant	9/12	1	NM_014326.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Aug 12, 2021

The c.847C>T (p.P283S) alteration is located in exon 9 (coding exon 8) of the DAPK2 gene. This alteration results from a C to T substitution at nucleotide position 847, causing the proline (P) at amino acid position 283 to be replaced by a serine (S). 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	Benign	0.33
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.15	T;T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.;.;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.0	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.8	D;D;.;D
REVEL	Benign	0.23
Sift	Benign	0.10	T;T;.;T
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.98	D;D;.;.
Vest4		0.66
MutPred		0.75		Gain of MoRF binding (P = 0.0512);Gain of MoRF binding (P = 0.0512);Gain of MoRF binding (P = 0.0512);Gain of MoRF binding (P = 0.0512);
MVP		0.74
MPC		0.37
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.61
gMVP		0.62

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: chr15-64217026;