chr15-63971425-T-G

Position:

• chr15-63971425-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_014326.5(DAPK2):​c.451A>C​(p.Lys151Gln) variant causes a missense, splice region 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. 3/3 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: 0.00040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DAPK2 NM_014326.5 missense, splice_region
• Scores: Splicing: ADA: 0.02932
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAPK2	NM_014326.5	c.451A>C	p.Lys151Gln	missense_variant, splice_region_variant	4/12	ENST00000457488.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAPK2	ENST00000457488.6	c.451A>C	p.Lys151Gln	missense_variant, splice_region_variant	4/12	1	NM_014326.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000403 AC: 584 AN: 1449412 Hom.: 0 Cov.: 31 AF XY: 0.000355 AC XY: 256 AN XY: 721508

Gnomad4 AFR exome AF: 0.000241

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000472

Gnomad4 OTH exome AF: 0.000384

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

Feb 28, 2023

The c.451A>C (p.K151Q) alteration is located in exon 4 (coding exon 3) of the DAPK2 gene. This alteration results from a A to C substitution at nucleotide position 451, causing the lysine (K) at amino acid position 151 to be replaced by a glutamine (Q). 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	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;.;.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.0	H;H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D;D;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.92
MutPred		0.82		Loss of methylation at K151 (P = 0.0253);Loss of methylation at K151 (P = 0.0253);Loss of methylation at K151 (P = 0.0253);Loss of methylation at K151 (P = 0.0253);
MVP		0.97
MPC		0.73
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.94
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.029
dbscSNV1_RF	Benign	0.24
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-64263624;