9-87605066-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004938.4(DAPK1):c.175G>C(p.Glu59Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DAPK1 NM_004938.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.93

Genes affected

DAPK1 (HGNC:2674): (death associated protein kinase 1) Death-associated protein kinase 1 is a positive mediator of gamma-interferon induced programmed cell death. DAPK1 encodes a structurally unique 160-kD calmodulin dependent serine-threonine kinase that carries 8 ankyrin repeats and 2 putative P-loop consensus sites. It is a tumor suppressor candidate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DAPK1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAPK1	NM_004938.4	c.175G>C	p.Glu59Gln	missense_variant	3/26	ENST00000408954.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAPK1	ENST00000408954.8	c.175G>C	p.Glu59Gln	missense_variant	3/26	2	NM_004938.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Dec 21, 2022

The c.175G>C (p.E59Q) alteration is located in exon 3 (coding exon 2) of the DAPK1 gene. This alteration results from a G to C substitution at nucleotide position 175, causing the glutamic acid (E) at amino acid position 59 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.085	T;T;.;T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.4	L;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.4	N;N;N;N;.;N
REVEL	Benign	0.24
Sift	Benign	0.29	T;T;T;T;.;T
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		0.95	P;P;.;P;P;.
Vest4		0.65
MutPred		0.37		Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);
MVP		0.62
MPC		0.60
ClinPred		0.75	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-90219981;