Genetic Variant NM_004938.4:c.91C>G (chr9-87604982-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_004938.4(DAPK1):c.91C>G(p.Arg31Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DAPK1
NM_004938.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.89

Publications

0 publications found

Variant links:

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

DAPK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DAPK1	NM_004938.4	MANE Select	c.91C>G	p.Arg31Gly	missense	Exon 3 of 26	NP_004929.2	P53355-1
DAPK1	NM_001288729.2		c.91C>G	p.Arg31Gly	missense	Exon 3 of 26	NP_001275658.1	P53355-1
DAPK1	NM_001288730.2		c.91C>G	p.Arg31Gly	missense	Exon 3 of 26	NP_001275659.1	P53355-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DAPK1	ENST00000408954.8	TSL:2 MANE Select	c.91C>G	p.Arg31Gly	missense	Exon 3 of 26	ENSP00000386135.3	P53355-1
DAPK1	ENST00000358077.9	TSL:1	c.91C>G	p.Arg31Gly	missense	Exon 3 of 26	ENSP00000350785.5	P53355-1
DAPK1	ENST00000472284.5	TSL:1	c.91C>G	p.Arg31Gly	missense	Exon 3 of 26	ENSP00000417076.1	P53355-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.2

PhyloP100

4.9

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.27

Sift

Benign

0.071

Sift4G

Uncertain

0.014

Polyphen

0.92

Vest4

0.94

MutPred

0.58

Loss of MoRF binding (P = 0.02)

MVP

0.78

MPC

0.88

ClinPred

0.98

GERP RS

5.0

Varity_R

0.81

gMVP

0.85

Mutation Taster

=23/77

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over