4-150224502-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040260.4(DCLK2):c.1243T>G(p.Ser415Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,458,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DCLK2 NM_001040260.4 missense, splice_region
• Scores: Splicing: ADA: 0.3338
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.80

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1551609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCLK2	NM_001040260.4	c.1243T>G	p.Ser415Ala	missense_variant, splice_region_variant	8/16	ENST00000296550.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCLK2	ENST00000296550.12	c.1243T>G	p.Ser415Ala	missense_variant, splice_region_variant	8/16	1	NM_001040260.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458412 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 28, 2023

The c.1294T>G (p.S432A) alteration is located in exon 9 (coding exon 9) of the DCLK2 gene. This alteration results from a T to G substitution at nucleotide position 1294, causing the serine (S) at amino acid position 432 to be replaced by an alanine (A). 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	Benign	0.069
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.037	T;T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.080
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.42	N;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.4	N;.;N;N
REVEL	Benign	0.039
Sift	Benign	0.12	T;.;T;T
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.0070	B;.;B;B
Vest4		0.13
MutPred		0.39		Loss of phosphorylation at S415 (P = 0.0795);.;.;.;
MVP		0.55
MPC		0.67
ClinPred		0.74	D
GERP RS		5.8
Varity_R		0.24
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.33
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: -1

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: chr4-151145654;