chr9-87640823-T-G

Variant names:

• chr9-87640823-T-G
• rs555981502
• NM_004938.4:c.804T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004938.4(DAPK1):​c.804T>G​(p.Asp268Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: DAPK1 NM_004938.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0260
• Publications: 2 publications found

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]

DAPK1 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14159718).
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004938.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAPK1	NM_004938.4	MANE Select	c.804T>G	p.Asp268Glu	missense	Exon 9 of 26	NP_004929.2	P53355-1
	DAPK1	NM_001288729.2		c.804T>G	p.Asp268Glu	missense	Exon 9 of 26	NP_001275658.1	P53355-1
	DAPK1	NM_001288730.2		c.804T>G	p.Asp268Glu	missense	Exon 9 of 26	NP_001275659.1	P53355-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAPK1	ENST00000408954.8	TSL:2 MANE Select	c.804T>G	p.Asp268Glu	missense	Exon 9 of 26	ENSP00000386135.3	P53355-1
	DAPK1	ENST00000358077.9	TSL:1	c.804T>G	p.Asp268Glu	missense	Exon 9 of 26	ENSP00000350785.5	P53355-1
	DAPK1	ENST00000472284.5	TSL:1	c.804T>G	p.Asp268Glu	missense	Exon 9 of 26	ENSP00000417076.1	P53355-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249526 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.54	N
PhyloP100		-0.026
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.27
Sift	Benign	0.53	T
Sift4G	Benign	0.61	T
Polyphen		0.90	P
Vest4		0.29
MutPred		0.52		Loss of MoRF binding (P = 0.1136)
MVP		0.83
MPC		0.38
ClinPred		0.11	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.62
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs555981502; hg19: chr9-90255738;