NM_001040260.4:c.350C>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001040260.4(DCLK2):c.350C>A(p.Pro117His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. P117L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

DCLK2
NM_001040260.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.79

Publications

0 publications found

Variant links:

Genes affected

DCLK2 (HGNC:19002): (doublecortin like kinase 2) This gene encodes a member of the protein kinase superfamily and the doublecortin family. The protein encoded by this gene contains two N-terminal doublecortin domains, which bind microtubules and regulate microtubule polymerization, a C-terminal serine/threonine protein kinase domain, which shows substantial homology to Ca2+/calmodulin-dependent protein kinase, and a serine/proline-rich domain in between the doublecortin and the protein kinase domains, which mediates multiple protein-protein interactions. The microtubule-polymerizing activity of the encoded protein is independent of its protein kinase activity. Mouse studies show that the DCX gene, another family member, and this gene share function in the establishment of hippocampal organization and that their absence results in a severe epileptic phenotype and lethality, as described in human patients with lissencephaly. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Sep 2010]

DCLK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DCLK2	NM_001040260.4	MANE Select	c.350C>A	p.Pro117His	missense	Exon 1 of 16	NP_001035350.2	Q8N568-1
DCLK2	NM_001040261.5		c.350C>A	p.Pro117His	missense	Exon 1 of 17	NP_001035351.4	Q8N568-3
DCLK2	NM_001410852.1		c.350C>A	p.Pro117His	missense	Exon 1 of 16	NP_001397781.1	Q8N568-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DCLK2	ENST00000296550.12	TSL:1 MANE Select	c.350C>A	p.Pro117His	missense	Exon 1 of 16	ENSP00000296550.7	Q8N568-1
DCLK2	ENST00000302176.8	TSL:1	c.350C>A	p.Pro117His	missense	Exon 1 of 17	ENSP00000303887.8	Q8N568-3
DCLK2	ENST00000411937.6	TSL:1	n.350C>A		non_coding_transcript_exon	Exon 1 of 17	ENSP00000401916.2	G5E9L9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1436720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32914

American (AMR)

AF:

0.00

AC:

AN:

41186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25608

East Asian (EAS)

AF:

0.00

AC:

AN:

38294

South Asian (SAS)

AF:

0.00

AC:

AN:

82480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099764

Other (OTH)

AF:

0.0000168

AC:

AN:

59462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

PhyloP100

7.8

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.93

Sift

Benign

0.034

Sift4G

Uncertain

0.030

Polyphen

1.0

Vest4

0.72

MutPred

0.76

Loss of catalytic residue at N115 (P = 0.1032)

MVP

0.94

MPC

1.0

ClinPred

0.99

GERP RS

4.2

PromoterAI

-0.067

Neutral

(source)

Varity_R

0.85

gMVP

0.77

Mutation Taster

=41/59

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over